Information

Fatty acid oxidation in adrenal medulla?


Why adrenal medulla can not utilise fatty acids for generation of energy? What could be the benefit for not having ability to use fatty acids?

Refrence 1

Refrence 2


Disorders of the Adrenal Medulla

The adrenal medulla secretes catecholamines (epinephrine, norepinephrine, and dopamine). The catecholamines help prepare the individual to deal with emergency situations. The major disorder of the adrenal medulla is pheochromocytoma, a neoplasm characterized by excessive catecholamine secretion.

Normal Structure & Function of the Adrenal Medulla

Anatomy

The adrenal medulla is the reddish-brown central portion of the adrenal gland. Accessory medullary tissue is sometimes located in the retroperitoneum near the sympathetic ganglia or along the abdominal aorta (paraganglia) (Figure 12–1).

Figure 12–1

Anatomic distribution of extra-adrenal chromaffin tissue in the newborn. (Redrawn, with permission, from Coupland R. The Natural History of the Chromaffin Cell. Longman, Green, 1965.)

Histology

The adrenal medulla is made up of polyhedral cells arranged in cords or clumps. Embryologically, the adrenal medullary cells derive from neural crest cells. Medullary cells are innervated by cholinergic preganglionic nerve fibers that reach the gland via the splanchnic nerves. The adrenal medulla can be regarded as a specialized sympathetic ganglion, where preganglionic sympathetic nerve fibers (using acetylcholine as a neurotransmitter) directly make contact with postganglionic cells, which secrete catecholamines (mainly epinephrine) directly into the circulation. This relationship is analogous to the other sympathetic paraganglions, which connect preganglionic cholinergic sympathetic nerve fibers with postganglionic fibers using catecholamines (mainly norepinephrine) as neurotransmitters. Medullary parenchymal cells accumulate and store their hormone products in prominent, dense secretory granules, 150–350 nm in diameter. Histologically, these cells and granules have a high affinity for chromium salts ( chromaffin reaction ) and thus are called chromaffin cells and contain chromaffin granules. The granules contain the catecholamines epinephrine and norepinephrine. Morphologically, two types of medullary cells can be distinguished: epinephrine-secreting cells, which have larger, less dense granules, and norepinephrine-secreting cells, which have smaller, very dense granules. Separate dopamine-secreting cells have not been identified. Ninety percent of medullary cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type.

Physiology

The catecholamines help to regulate metabolism, contractility of cardiac and smooth muscle, and neurotransmission.

Formation, Secretion, & Metabolism of Catecholamines

The adrenal medulla secretes three catecholamines: epinephrine, norepinephrine, and dopamine. Secretion occurs after release of acetylcholine from the preganglionic neurons that innervate the medullary cells. The major biosynthetic pathways and hormonal intermediates for the catecholamines are shown in Figure 12–2. In humans, most (80%) of the catecholamine output of the adrenal medulla is epinephrine. Norepinephrine is principally found in paraganglionic nerve endings of the sympathetic nervous system and in the CNS, where it functions as a major neurotransmitter.

Figure 12–2

Biosynthesis and catabolism of catecholamines. The catecholamines are synthesized from tyrosine (TYR). The enzyme catechol- O -methyltransferase (COMT) generates metanephrine (MN) from epinephrine (E) and normetanephrine (NM) from norepinephrine. COMT is constitutively active in pheochromocytomas and paragangliomas and release of these substances is constant rather than episodic. (AADC, aromatic L -amino acid decarboxylase DA, dopamine DBH, dopamine beta-hydroxylase DOPAC, dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine NE, norepinephrine PNMT, phenylethanolamine N -methyltransferase VMA, vanillylmandelic acid.)

Approximately 70% of the epinephrine and norepinephrine and 95% of the dopamine found in plasma are conjugated to sulfate and inactive. In the supine state, the normal plasma level of free epinephrine is about 30 pg/mL (0.16 nmol/L) there is a 50–100% increase on standing. The normal plasma level of free norepinephrine is about 300 pg/mL (1.8 nmol/L), and the plasma free dopamine level is about 35 pg/mL (0.23 nmol/L).

Most catecholamine metabolism takes place within the same cells where they are synthesized, mainly because of leakage of catecholamines from vesicular stores into the cytoplasm. These vesicular stores exist in a dynamic equilibrium, with outward passive leakage counterbalanced by inward active transport that is controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase in the cytoplasm leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes is dependent on the dynamics of the vesicular-axoplasmic monoamine exchange and an enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol. Subsequent extraneuronal O -methylation leads to production of 3-methoxy-4-hydroxyphenylglycol, and its oxidation in the liver catalyzed by alcohol and aldehyde dehydrogenases leads to formation of vanillylmandelic acid (VMA). Compared with intraneuronal deamination, extraneuronal O -methylation of norepinephrine and epinephrine to metanephrines represents minor pathways of metabolism.

The single largest source of metanephrine is the adrenal medulla. In the circulation, the catecholamines have a short half-life of about 2 min. Normally, only very small quantities of free epinephrine (about 6 μg/d) and norepinephrine (about 30 μg/d) are excreted, but about 700 μg of VMA is excreted daily.

Regulation of Catecholamine Secretion

Physiologic stimuli affect medullary secretion through the nervous system. Medullary cells secrete catecholamines after release of acetylcholine from the preganglionic neurons that innervate them. Catecholamine secretion is low in the basal state and is reduced even further during sleep. In emergency situations, there is increased adrenal catecholamine secretion as part of a generalized sympathetic discharge that serves to prepare the individual for stress (“fight-or-flight” response). Physiological stress such as psychological, physical (eg, mechanical, thermal), and metabolic (eg, hypoglycemia, exercise) stress leads to catecholamine secretion.

Mechanism of Action of Catecholamines

The effects of epinephrine and norepinephrine are mediated by their actions on two classes of receptors: α- and β-adrenergic receptors (Table 12–1). Alpha receptors are subdivided into α 1 and α 2 receptors and β receptors into β 1 , β 2 , and β 3 receptors. Alpha 1 receptors mediate smooth muscle contraction in blood vessels and the genitourinary (GU) tract and increase glycogenolysis. Alpha 2 receptors mediate smooth muscle relaxation in the GI tract and vasoconstriction of some blood vessels. Alpha 2 receptors also decrease insulin secretion. Beta 1 receptors mediate an increased rate and force of myocardial contraction and stimulate lipolysis and renin release. Beta 2 receptors mediate smooth muscle relaxation in the bronchi, blood vessels, GU tract, and GI tract and increase hepatic gluconeogenesis and glycogenolysis, muscle glycogenolysis, and release of insulin and glucagon.
























































































































































Organ or Tissue Adrenergic Receptor Effect
Heart (myocardium) β 1 Increased force of contraction (inotropic)
α 1 , β 1 Increased rate of contraction (chronotropic)
β 1 Increased excitability (predisposes to arrhythmia)
β 1 Increased AV nodal conduction velocity
Blood vessels (vascular smooth muscle) α 1 , α 2 Vasoconstriction, hypertension
β 2 Vasodilation
Kidney (juxtaglomerular cells) β 1 Increased renin release
β 2 Increased peripheral conversion of T 4 to T 3
Gut (intestinal smooth muscle) α 1 , β 2 Increased sphincter tone (hyperpolarization) decreased motility (relaxation)
β 3 Increased motility
Pancreas (B cells) α 2 Decreased insulin release
Decreased glucagon release
β 2 Increased insulin release
Increased glucagon release
Liver α 1 , β 2 Increased gluconeogenesis
Increased glycogenolysis
Increased peripheral conversion of T 4 to T 3
Adipose tissue α 2 Decreased lipolysis
β 1 , β 3 Increased lipolysis
Skin (eg, apocrine glands on hands, axillas hair) α 1 Increased sweating
Increased piloerection
Lung (bronchial smooth muscle) β 2 Dilation of bronchi and bronchioles
Uterus (genitourinary smooth muscle) α 1 Increased contraction of gravid uterus. Decreased contraction of nongravid uterus (relaxation)
β 2 Relaxation
Bladder (genitourinary smooth muscle) α 1 Contraction
β 2 Relaxation
Prostate α 1 Increased contraction and ejaculation
Skeletal muscle β 2 Increased muscle contraction speed
Increased glycogenolysis
Increased release of lactic acid
Platelets α 2 Aggregation
CNS α Increased alertness, anxiety, fear
Eye α 1 Increased ciliary muscle contraction (pupillary dilation)
Peripheral nerves β 2 Increased conduction velocity
Most tissues β 1 , β 3 Increased calorigenesis
Increased metabolic rate

Intracellular post-receptor signaling is different for each subclass of adrenergic receptor. Stimulation of α 1 -adrenergic receptors results in an increase in intracellular Ca 2+ concentrations. First, there is activation of phospholipase C by the guanine nucleotide binding stimulatory protein, G s . Phospholipase C hydrolyzes the membrane-bound phospholipid, phosphatidylinositol-4,5-bisphosphate, to generate two second messengers: diacylglycerol and inositol-1,4,5-trisphosphate. Diacylglycerol in turn activates protein kinase C, which phosphorylates various cellular substrates. Inositol-1,4,5-trisphosphate stimulates release of intracellular Ca 2+ , which then initiates various cellular responses.

Activation of α 2 -adrenergic receptors results in a decrease in intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). The mechanism involves receptor interaction with an inhibitory G protein, G i , leading to inhibition of adenylyl cyclase. The fall in cAMP level leads to a decrease in activity of the cAMP-dependent protein kinase A. The G i protein also stimulates K + channels and inhibits voltage-sensitive calcium channels.

On the other hand, β-adrenergic receptors stimulate adenylyl cyclase through the mediation of G s . Activation of β-adrenergic receptors thus leads to an increase in cAMP, activation of the cAMP-dependent protein kinase A, and consequent phosphorylation of various cellular proteins. The G s protein can also directly activate voltage-sensitive Ca 2+ channels in the plasma membrane of cardiac and skeletal muscle.

The α 1 – and β 1 -adrenergic receptors are generally found in organs and tissues (eg, heart and gut) that are heavily innervated by—and situated so as to be readily activated by stimulation of—the sympathetic nerves. The α 1 – and β 1 -adrenergic receptors are preferentially stimulated by norepinephrine, especially that released by nerve endings. In contrast, the α 2 – and β 2 -adrenergic receptors are generally situated in postjunctional sites in organs and tissues (eg, uterine and bronchial skeletal muscle) remote from sites of norepinephrine release. The α 2 – and β 2 -adrenergic receptors are preferentially stimulated by circulating catecholamines, especially epinephrine.

Differences in tissue distribution, accessibility by nerve fibers, preferences for epinephrine versus norepinephrine, and differences in postreceptor signaling are thus responsible for the diverse effects of catecholamines in an organ- and cell-specific manner.

Effects of Catecholamines

The catecholamines have been termed fight-or-flight hormones because their effects on the heart, blood vessels, smooth muscle, and metabolism assist the organism in responding to stress. The principal physiologic effects of the catecholamines are shown in Table 12–1.

In the peripheral circulation, norepinephrine produces vasoconstriction in most organs (via α 1 receptors). Epinephrine produces vasodilation via β 2 receptors in skeletal muscle and liver and vasoconstriction elsewhere. The former usually outweighs the latter, and for that reason epinephrine usually lowers total peripheral resistance.

Norepinephrine causes both systolic and diastolic blood pressures to rise. The rise in blood pressure stimulates the carotid and aortic baroreceptors, resulting in reflex bradycardia and a fall in cardiac output. Epinephrine causes a widening of pulse pressure but does not stimulate the baroreceptors to the same degree, so the pulse rises and cardiac output increases.

Hence, pheochromocytomas or other tumors of the adrenal medulla, which usually secrete norepinephrine, lead to vasoconstriction and an increase in blood pressure.

The effects of catecholamines on metabolism include effects on glycogenolysis, lipolysis, and insulin secretion, mediated by both α- and β-adrenergic receptors. These metabolic effects result primarily from the action of epinephrine on four target tissues: liver, muscle, pancreas, and adipose tissue (see Table 12–1). The result is an increase in the levels of circulating glucose and free fatty acids. The increased supply of these two substances helps provide an adequate supply of metabolic fuel to the nervous system and muscle during physiologic stress.

The amount of circulating plasma epinephrine and norepinephrine needed to produce these various effects has been determined by infusing the catecholamines into resting subjects. For norepinephrine, the threshold for the cardiovascular and metabolic effects is a plasma level of about 1500 pg/mL, or about five times the basal level. In normal individuals, the plasma norepinephrine level rarely exceeds this threshold. However, for epinephrine, the threshold for tachycardia occurs at a plasma level of about 50 pg/mL, or about twice the basal level. The threshold for increasing systolic blood pressure and lipolysis is at about 75 pg/mL for increasing glucose and lactate, about 150 pg/mL and for increasing insulin secretion, about 40 pg/mL. In healthy individuals, plasma epinephrine levels often exceed these thresholds.

The physiologic effect of circulating dopamine is unknown. Centrally, dopamine acts to inhibit prolactin secretion. Peripherally, in small doses, injected dopamine produces renal vasodilation, probably by binding to a specific dopaminergic receptor. In moderate doses, it also produces vasodilation of the mesenteric and coronary circulation and vasoconstriction peripherally. It has a positive inotropic effect on the heart, mediated by action on the β 1 -adrenergic receptors. Moderate to large doses of dopamine increase the systolic blood pressure without affecting diastolic pressure.


The Adrenal Medulla & Adrenal Cortex

Name the three catecholamines secreted by the adrenal medulla and summarize their biosynthesis, metabolism, and function.

List the stimuli that increase adrenal medullary secretion.

Differentiate between C 18 , C 19 , and C 21 steroids and give examples of each.

Outline the steps involved in steroid biosynthesis in the adrenal cortex.

Name the plasma proteins that bind adrenocortical steroids and discuss their physiologic role.

Name the major site of adrenocortical hormone metabolism and the principal metabolites produced from glucocorticoids, adrenal androgens, and aldosterone.

Describe the mechanisms by which glucocorticoids and aldosterone produce changes in cellular function.

List and briefly describe the physiologic and pharmacologic effects of glucocorticoids.

Contrast the physiologic and pathologic effects of adrenal androgens.

Describe the mechanisms that regulate secretion of glucocorticoids and adrenal sex hormones.

List the actions of aldosterone and describe the mechanisms that regulate aldosterone secretion.

Describe the main features of the diseases caused by excess or deficiency of each of the hormones of the adrenal gland.

INTRODUCTION

There are two endocrine organs in the adrenal gland, one surrounding the other. The main secretions of the inner adrenal medulla (Figure 20–1) are the catecholamines epinephrine, norepinephrine, and dopamine the outer adrenal cortex secretes steroid hormones.

FIGURE 20–1

Human adrenal glands. Adrenocortical tissue is yellow adrenal medullary tissue is orange. Note the location of the adrenals at the superior pole of each kidney. Also shown are extra-adrenal sites (gray) at which cortical and medullary tissue is sometimes found. (Reproduced with permission from Williams RH: Textbook of Endocrinology , 4th ed. St. Louis, MO: Saunders 1968.)

The adrenal medulla is in effect a sympathetic ganglion in which the postganglionic neurons have lost their axons and become secretory cells. The cells secrete when stimulated by the preganglionic nerve fibers that reach the gland via the splanchnic nerves. Adrenal medullary hormones work mostly to prepare the body for emergencies, the so-called “fight-or-flight” responses.

The adrenal cortex secretes glucocorticoids, steroids with widespread effects on the metabolism of carbohydrate and protein and a mineralocorticoid essential to the maintenance of Na + balance and extracellular fluid (ECF) volume. It is also a secondary site of androgen synthesis, secreting sex hormones such as testosterone, which can exert effects on reproductive function. Mineralocorticoids and the glucocorticoids are necessary for survival. Adrenocortical secretion is controlled primarily by adrenocorticotropic hormone (ACTH) from the anterior pituitary, but mineralocorticoid secretion is also subject to independent control by circulating factors, of which the most important is angiotensin II, a peptide formed in the bloodstream by the action of renin.

ADRENAL MORPHOLOGY

The adrenal medulla, which constitutes 28% of the mass of the adrenal gland, is made up of interlacing cords of densely innervated granule-containing cells that abut on venous sinuses. Two cell types can be distinguished morphologically: an epinephrine-secreting type that has larger, less dense granules and a norepinephrine-secreting type in which smaller, very dense granules fail to fill the vesicles in which they are contained. In humans, 90% of the cells are the epinephrine-secreting type and 10% are the norepinephrine-secreting type. The type of cell that secretes dopamine is unknown. Paraganglia, small groups of cells resembling those in the adrenal medulla, are found near the thoracic and abdominal sympathetic ganglia (Figure 20–1).

In adult mammals, the adrenal cortex is divided into three zones (Figure 20–2) . The outer zona glomerulosa is made up of whorls of cells that are continuous with the columns of cells that form the zona fasciculata. These columns are separated by venous sinuses. The inner portion of the zona fasciculata merges into the zona reticularis, where the cell columns become interlaced in a network. The zona glomerulosa makes up 15% of the mass of the adrenal gland the zona fasciculata, 50% and the zona reticularis, 7%. The adrenocortical cells contain abundant lipid, especially in the outer portion of the zona fasciculata. All three cortical zones secrete corticosterone, but the active enzymatic mechanism for aldosterone biosynthesis is limited to the zona glomerulosa, whereas the enzymatic mechanisms for forming cortisol and sex hormones are found in the two inner zones. Furthermore, subspecialization occurs within the inner two zones, with the zona fasciculata secreting mostly glucocorticoids and the zona reticularis secreting mainly sex hormones.

FIGURE 20–2

Section through an adrenal gland showing both the medulla and the zones of the cortex, as well as the hormones they secrete. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms of Body Function , 11th ed. New York, NY: McGraw-Hill 2008.)

Arterial blood reaches the adrenal from many small branches of the phrenic and renal arteries and the aorta. From a plexus in the capsule, blood flows through the cortex to the sinusoids of the medulla. The medulla is also supplied by a few arterioles that pass directly to it from the capsule. In most species, including humans, blood from the medulla flows into a central adrenal vein. The blood flow through the adrenal is large, as it is in most endocrine glands.

During fetal life, the human adrenal is large and under pituitary control, but the three zones of the permanent cortex represent only 20% of the gland. The remaining 80% is the large fetal adrenal cortex, which undergoes rapid degeneration at the time of birth. A major function of this fetal adrenal is synthesis and secretion of sulfate conjugates of androgens that are converted in the placenta to estrogens (see Chapter 22). No structure is comparable to the human fetal adrenal in laboratory animals.

An important function of the zona glomerulosa, in addition to aldosterone synthesis, is the formation of new cortical cells. The adrenal medulla does not regenerate, but when the inner two zones of the cortex are removed, a new zona fasciculata and zona reticularis regenerate from glomerular cells attached to the capsule. Small capsular remnants regrow large pieces of adrenocortical tissue. Immediately after hypophysectomy, the zona fasciculata and zona reticularis begin to atrophy, whereas the zona glomerulosa is unchanged because of the action of angiotensin II on this zone. The ability to secrete aldosterone and conserve Na + is normal for some time after hypophysectomy, but in long-standing hypopituitarism, aldosterone deficiency may develop, apparently because of the absence of a pituitary factor that maintains the responsiveness of the zona glomerulosa. Injections of ACTH and stimuli that cause endogenous ACTH secretion produce hypertrophy of the zona fasciculata and zona reticularis but actually decrease, rather than increase, the size of the zona glomerulosa.

The cells of the adrenal cortex contain large amounts of smooth endoplasmic reticulum, which is involved in the steroid-forming process. Other steps in steroid biosynthesis occur in the mitochondria. The structure of steroid-secreting cells is very similar throughout the body. The typical features of such cells are shown in Figure 20–3 .

FIGURE 20–3

Schematic overview of the structures of steroid-secreting cells and the intracellular pathway of steroid synthesis. LDL, low-density lipoprotein PKA, protein kinase A. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms of Body Function , 11th ed. New York, NY: McGraw-Hill 2008.)

ADRENAL MEDULLA: STRUCTURE & FUNCTION OF MEDULLARY HORMONES

CATECHOLAMINES

Norepinephrine, epinephrine, and small amounts of dopamine are synthesized by the adrenal medulla. Cats and some other species secrete mainly norepinephrine, but in dogs and humans, most of the catecholamine output in the adrenal vein is epinephrine. Norepinephrine also enters the circulation from noradrenergic nerve endings.

The structures of norepinephrine, epinephrine, and dopamine and the pathways for their biosynthesis and metabolism are discussed in Chapter 7. Norepinephrine is formed by hydroxylation and decarboxylation of tyrosine, and epinephrine by methylation of norepinephrine. Phenylethanolamine-N-methyltransferase (PNMT), the enzyme that catalyzes the formation of epinephrine from norepinephrine, is found in appreciable quantities only in the brain and the adrenal medulla. Adrenal medullary PNMT is induced by glucocorticoids. Although relatively large amounts are required, the glucocorticoid concentration is high in the blood draining from the cortex to the medulla. After hypophysectomy, the glucocorticoid concentration of this blood falls and epinephrine synthesis is decreased. In addition, glucocorticoids are apparently necessary for the normal development of the adrenal medulla in 21β-hydroxylase deficiency, glucocorticoid secretion is reduced during fetal life and the adrenal medulla is dysplastic. In untreated 21β-hydroxylase deficiency, circulating catecholamines are low after birth.

In plasma, about 95% of the dopamine and 70% of the norepinephrine and epinephrine are conjugated to sulfate. Sulfate conjugates are inactive and their function is unsettled. In recumbent humans, the normal plasma level of free norepinephrine is about 300 pg/mL (1.8 nmol/L). On standing, the level increases 50–100% (Figure 20–4) . The plasma norepinephrine level is generally unchanged after adrenalectomy, but the free epinephrine level, which is normally about 30 pg/mL (0.16 nmol/L), falls to essentially zero. The epinephrine found in tissues other than the adrenal medulla and the brain is for the most part absorbed from the bloodstream rather than synthesized in situ. Interestingly, low levels of epinephrine reappear in the blood some time after bilateral adrenalectomy, and these levels are regulated like those secreted by the adrenal medulla. They may come from cells such as the intrinsic cardiac adrenergic (ICA) cells (see Chapter 13), but their exact source is unknown.

FIGURE 20–4

Norepinephrine and epinephrine levels in human venous blood in various physiologic and pathologic states. Note that the horizontal scales are different. The numbers to the left in parentheses are the numbers of subjects tested. In each case, the vertical dashed line identifies the threshold plasma concentration at which detectable physiologic changes are observed. (Modified and reproduced with permission from Cryer PE: Physiology and pathophysiology of the human sympathoadrenal neuroendocrine system. N Engl J Med 1980 Aug 21 303(8):436–444.)

Plasma dopamine levels are normally very low, about 0.13 nmol/L. Most plasma dopamine is thought to be derived from sympathetic noradrenergic ganglia.

The catecholamines have a half-life of about 2 min in the circulation. For the most part, they are methoxylated and then oxidized to 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid [VMA] see Chapter 7). About 50% of the secreted catecholamines appear in the urine as free or conjugated metanephrine and normetanephrine, and 35% as VMA. Only small amounts of free norepinephrine and epinephrine are excreted. In normal humans, about 30 μg of norepinephrine, 6 μg of epinephrine, and 700 μg of VMA are excreted per day.

OTHER SUBSTANCES SECRETED BY THE ADRENAL MEDULLA

In the medulla, norepinephrine and epinephrine are stored in granules with ATP. The granules also contain chromogranin A (see Chapter 7). Secretion is initiated by acetylcholine released from the preganglionic neurons that innervate the secretory cells. Acetylcholine activates cation channels allowing Ca 2+ to enter the cells from the ECF and trigger the exocytosis of the granules. In this manner, catecholamines, ATP, and proteins from the granules are all released into the blood together.

Epinephrine-containing cells of the medulla also contain and secrete opioid peptides (see Chapter 7). The precursor molecule is preproenkephalin. Most of the circulating metenkephalin comes from the adrenal medulla. The circulating opioid peptides do not cross the blood–brain barrier.

Adrenomedullin, a vasodepressor polypeptide found in the adrenal medulla, is discussed in Chapter 32.

EFFECTS OF EPINEPHRINE & NOREPINEPHRINE

In addition to mimicking the effects of noradrenergic nervous discharge, norepinephrine and epinephrine exert metabolic effects that include glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids (FFA), increased plasma lactate, and stimulation of the metabolic rate. The effects of norepinephrine and epinephrine are brought about by actions on two classes of receptors: α- and β-adrenergic receptors. α-Receptors are subdivided into two groups, α 1 and α 2 receptors, and β-receptors into three groups, β 1 , β 2 , and β 3 receptors (see Chapter 7). There are three subtypes of α 1 -receptors and three subtypes of α 2 -receptors (see Table 7–2).

Norepinephrine and epinephrine both increase the force and rate of contraction of the isolated heart. These responses are mediated by β 1 -receptors. The catecholamines also increase myocardial excitability, causing extrasystoles and, occasionally, more serious cardiac arrhythmias. Norepinephrine produces vasoconstriction in most if not all organs via α 1 -receptors, but epinephrine dilates the blood vessels in skeletal muscle and the liver via β 2 -receptors. This usually overbalances the vasoconstriction produced by epinephrine elsewhere, and the total peripheral resistance drops. When norepinephrine is infused slowly in normal animals or humans, the systolic and diastolic blood pressures rise. The hypertension stimulates the carotid and aortic baroreceptors, producing reflex bradycardia that overrides the direct cardioacceleratory effect of norepinephrine. Consequently, cardiac output per minute falls. Epinephrine causes a widening of the pulse pressure but because baroreceptor stimulation is insufficient to obscure the direct effect of the hormone on the heart, cardiac rate and output increase. These changes are summarized in Figure 20–5 .

FIGURE 20–5

Circulatory changes produced in humans by the slow intravenous infusion of epinephrine and norepinephrine.

Catecholamines increase alertness (see Chapter 14). Epinephrine and norepinephrine are equally potent in this regard, although in humans epinephrine usually evokes more anxiety and fear.

The catecholamines have several different actions that affect blood glucose. Epinephrine and norepinephrine both cause glycogenolysis. They produce this effect via β-adrenergic receptors that increase cyclic adenosine monophosphate (cAMP), with activation of phosphorylase, and via α-adrenergic receptors that increase intracellular Ca 2+ (see Chapter 7). In addition, the catecholamines increase the secretion of insulin and glucagon via β-adrenergic mechanisms and inhibit the secretion of these hormones via α-adrenergic mechanisms.

Norepinephrine and epinephrine also produce a prompt rise in the metabolic rate that is independent of the liver and a smaller, delayed rise that is abolished by hepatectomy and coincides with the rise in blood lactate concentration. The initial rise in metabolic rate may be due to cutaneous vasoconstriction, which decreases heat loss and leads to a rise in body temperature, or to increased muscular activity, or both. The second rise is probably due to oxidation of lactate in the liver. Mice unable to make norepinephrine or epinephrine because their dopamine β-hydroxylase gene is knocked out are intolerant of cold, but surprisingly, their basal metabolic rate is elevated. The cause of this elevation is unknown.

When injected, epinephrine and norepinephrine cause an initial rise in plasma K + because of release of K + from the liver and then a prolonged fall in plasma K + because of an increased entry of K + into skeletal muscle that is mediated by β 2 -adrenergic receptors. Some evidence suggests that activation of α-receptors opposes this effect.

The increases in plasma norepinephrine and epinephrine that are needed to produce the various effects listed above have been determined by infusion of catecholamines in resting humans. In general, the threshold for the cardiovascular and the metabolic effects of norepinephrine is about 1500 pg/mL, that is, about five times the resting value (Figure 20–4). Epinephrine, on the other hand, produces tachycardia when the plasma level is about 50 pg/mL, that is, about twice the resting value. The threshold for increased systolic blood pressure and lipolysis is about 75 pg/mL the threshold for hyperglycemia, increased plasma lactate, and decreased diastolic blood pressure is about 150 pg/mL and the threshold for the α-mediated decrease in insulin secretion is about 400 pg/mL. Plasma epinephrine often exceeds these thresholds. On the other hand, plasma norepinephrine rarely exceeds the threshold for its cardiovascular and metabolic effects, and most of its effects are due to its local release from postganglionic sympathetic neurons. Most adrenal medullary tumors (pheochromocytomas) secrete norepinephrine or epinephrine or both and produce sustained hypertension. However, 15% of epinephrine-secreting tumors secrete this catecholamine episodically, producing intermittent bouts of palpitations, headache, glycosuria, and extreme systolic hypertension. These same symptoms are produced by intravenous injection of a large dose of epinephrine.

EFFECTS OF DOPAMINE

The physiologic function of the dopamine in the circulation is unknown. However, injected dopamine produces renal vasodilation, probably by acting on a specific dopaminergic receptor. It also produces vasodilation in the mesentery. Elsewhere, it produces vasoconstriction, probably by releasing norepinephrine, and it has a positive inotropic effect on the heart by an action on β 1 -adrenergic receptors. The net effect of moderate doses of dopamine is an increase in systolic pressure and no change in diastolic pressure. Because of these actions, dopamine is useful in the treatment of traumatic and cardiogenic shock (see Chapter 32).

Dopamine is made in the renal cortex. It causes natriuresis and may exert this effect by inhibiting renal Na, K, ATPase.


Adrenal gland

The adrenal glands are two small endocrine organs triangular to semilunar shape, located right on top of the kidneys and are enveloped by a fibrous capsule surrounded by adipose tissue. Each gland consists of two parts, the adrenal cortex and the adrenal medulla.

The adrenal cortex secretes corticosteroids and androgens and consists of three layers, namely:

Zona glomerulosa the outer layer, produces aldosterone which is important for the control of blood pressure. The cells are cuboidal to columnar in shape and arranged in rounded clumps, glomeruli, surrounded by sinusoidal capillaries. The round cell nucleus is darkly stained and the cytoplasm is acidophilic.

Zona fasciculata the middle and broadest layer and consists of glucocorticoids producing cells which are arranged in parallel cords, surrounded by sinusoid capillaries. The shapes of the cells are cuboidal or polygonal with a poorly stained cytoplasm. Lipid droplets give the cells a foamy appearance. The nucleus is round and darkly stained.

Zona reticularis the inner layer, consists of cells arranged in anastomosing cords, giving it a reticular pattern. These cells produce weak androgens and some glucocorticoids. The cells of the zona reticularis are smaller and darker stained than the ones in zona fasciculata.

The adrenal medulla is made up of nervous tissue and secretes catecholamines in response to neuronal signals. The most abundant cells in the medulla is the chromaffin cells. Cells of the adrenal medulla are innervated by presynaptic sympathetic neurons and release the catecholamines norepinephrine and epinephrine on direct response to nerve impulses. These chromaffin cells in the medulla are lightly stained basophilic cells that are arranged in ovoid clusters in close proximity to capillaries. A small number of sympathetic ganglion cells are commonly observed in the medulla, a large nucleus with prominent nucleoli.


Posterior Pituitary

The posterior pituitary is significantly different in structure from the anterior pituitary. It is a part of the brain, extending down from the hypothalamus, and contains mostly nerve fibers and neuroglial cells, which support axons that extend from the hypothalamus to the posterior pituitary. The posterior pituitary and the infundibulum together are referred to as the neurohypophysis.

The hormones antidiuretic hormone (ADH), also known as vasopressin, and oxytocin are produced by neurons in the hypothalamus and transported within these axons along the infundibulum to the posterior pituitary. They are released into the circulatory system via neural signaling from the hypothalamus. These hormones are considered to be posterior pituitary hormones, even though they are produced by the hypothalamus, because that is where they are released into the circulatory system. The posterior pituitary itself does not produce hormones, but instead stores hormones produced by the hypothalamus and releases them into the blood stream.


6 Organic Constituents Present in the Protoplasm (5963 Words) | Biology

Proteins (Gr„ proteuo = 1, occupy first place) are chains of amino acids linked by peptide bonds. Proteins are the most important organic compounds found in protoplasm in one form or other. The proteins with lipids and water represent the main constituents of protoplasm.

These consist of С, О, H, and N, which may form various combinations with phosphorus in nucleic acids and with S, Mg, Fe, etc. Protein molecules are large, composed of thousands of atoms. Their molecular weight is very high. They generally remain in a colloidal state.

They are the polymers of amino acids. On heating proteins become broken into their components — amino acids. The characteristic arrangement of an amino acid is exemplified by the presence of amino group (—NH2) and carboxyl group (—COOH). The amino group is basic and the carboxyl group is acidic. The amino acids are found freely in the cytoplasm and constitute the amino acid pool.

This is general molecular formula of amino acids. Here NH2 is the amino group,—COOH is the carboxyl group and R represents variety of chemical combinations which occur in different types of amino acids.

The amino acids differ from one another only in the side-chain, for example, the R in alanine has one carbon, while in leucine it has four carbons. The cytoplasm contains about 22 amino acids. Their names and the formulae of some of the amino acids are given below—

(9) Arginine, (10) Histidine, (11) Serine, (12) Threonine, (13) Cysteine, (14) Cystine, (15) Methionine, (16) Phenylalanine, (17) Tyrosine, (18) Tryptophan, (19) Proline, (20) Hydroxyproline, (21) Aspargine, and (22) Glutamine.

The amino acids of the protein molecule are united to one another by their respective amino and carboxyl groups, forming peptide bonds or linkage. —NH—CO— is called the peptide linkage or peptide bond. The formed molecule preserves its amphoteric character, since an acidic group is always at one end and a basic group is at the other, in addition to the lateral residues (radicals) which can be either basic or acidic.

A combination of two amino acids is a dipeptide. The chain of peptide bonds between amino acids is the backbone of the protein molecule and its primary structure. There are usually 6 kinds of amino acids as follows—

1. Monoamino-monocarboxylic amino acids (simple amino acids having one carboxyl group), e.g., glycine (Gly), alanine (Ala), valine (val), leucine (Leu), isoleucine (lieu).

2. Monoamino-dicarboxylic type (acidic amino acids having two carboxyl groups), e.g. glutamic (Glu), aspartic (Asp).

3. Diamino-monocarboxylic type (basic amino acids), e.g., arginine (Arg), Lysine (Lys), histidine.

4. Aromatic amino acids, e.g. tyrosine (Tyr), phenylalanine (Phe), atiu tryptophan (tryp).

5. Sulphur-containing amino acids, e.g., methionine (Met), cystine, and cysteine (Cys).

6. Hydroxyl-containing amino acids, e.g., threonine (Thr), and serine (ser).

Besides above amino acids there are found other amino acids which do not form proteins but occur as free form or in other combined forms. These are as follows as described by Mazur and Harrow (1971) —

(i) β-Alanine is a constituent of carnosine, pantothenic acid, anserine and muscle.

(ii) Citrulline is an intermediate product in urea biosynthesis.

(iii) Taurine is found in bile salts.

(iv) Creatine occurs in urea.

(v) Phosphoserine is found in casein and other enzymes.

(vi) Ornithine is an intermediary product of urea cycle.

(vii) Ergothionine is found in ergot and blood.

(viii) Hydroxylysine occurs in collagen and calf embryo.

(ix) Homocysteine is an intermediate in methionine metabolism.

(x) Cystathionine is also intermediate in methionine cycle.

(xi) y-Aminobutyric acid occurs in bacteria, yeast, brain, etc.

(xii) Dihydroxyphenylalanine is by-product of phenylalanine metabolism.

Some amino acids contain sulphur with their hydrogen molecules as in cystine. The combination of two amino acids by the peptide bond is called as dipeptide, whereas the condensation of few or several amino acids is called oligopeptide and polypeptide respectively. The various molecules of polypeptides unite to form the peptones, proteases and proteins.

[II] Structure of proteins:

Protein molecules consist of quite large polypeptide chains which remain folded and additional linkages between their amino acids. Degree of folding of protein molecules render them very complex structures. In other words, proteins exhibit different levels of organization namely primary, secondary, tertiary and quaternary.

In it, molecules of polypeptide chain remain ar­ranged in a single linear pattern by the peptide bonds. Here number, na­ture and sequence of amino acids in a polypeptide chain determine the primary structure of the proteins. Following primary structures of the protein have been determined—

(1) Ribonuclease structure has been described by Stein and coworkers. It has 124 amino acids residue.

(2) Human haemoglobin has 574 residues as described by Brounitzer and others.

(3) Human heart cytochrome С consists of 104 amino acids as dis­covered by Tuppy and Smith.

(4) Insulin structure has been described by Sanger being made up of two polypeptide chains held together by sulphur bridges. There are 51 amino acids.

2. Secondary structure:

It is determined by hydrogen bonding between the carboxyl oxygen and amide hydrogen atoms of constituent amino acids of the peptide chains. Thus, these proteins possess spirally or helically arranged chains of hundreds of amino acids in their molecules. The bonding (H) may take place either between different polypeptide chains or within the molecules of same polypeptide chain. Following types of helices are formed in the secondary proteins—

In it, peptide chain takes the form of a spiral stair case with 3 1/2 molecules of amino acids per turn. Various coils of the helix are held together by hydrogen bonds lying parallel to the main axis of fibre. Thus, a-helices provide flexibility, elasticity and stability to the peptide chain.

(b) β-helix or β-pleated sheet:

This structure involves hydrogen bonding between peptide chains at right angles to the main chains. Thus, β-helix fibres are not elastic because the polypeptide chains are already in extended form. However, such structures are quite strong and flexible as silk fibres, β-keratin of feathers and claws.

(c) Collagen helix:

This structure is more complicated formed by the twisting of three helices of polypeptide chain intertwined with each other so as to form a right-handed super helix. Triple strands or chains are further strengthened by hydrogen bonding between their hydroxyproline units. Thus, collagen helices are very strong and rigid structures and could not be easily extended or bent.

In it, bonding occurs between adjacent-R groups of amino acids of polypeptide chains with the result that peptide chains get further folded. Furthermore, these chains get folded over themselves. Various chains may remain held together by —S—S— bonds in their
molecule. Common examples are globular proteins (albumins, plasma globulins).

4. Quaternary structure:

These proteins contain two to many polypeptide chains of similar or different nature and remain bound together by weak covalent bonds such as haemoglobin which has two chains (a and (α and β-chain). Quaternary proteins may be of two types.

(i) In one category, protein molecules are composed of several dif­ferent peptide chains but having only one active site.

(ii) In the second category, proteins are composed of similar or identical units.

[III] Classification of proteins:

Proteins are of 3 kinds—simple, conjugated and derived.

A. Simple proteins:

These yield only amino acids or hydrolysis like histones, globulins, albumins, cereal proteins (glutenin, oryzein, zein, hordein, gliadin), animal tissues (e.g. keratin, elastin, gelatin, collagen), and protamines (of fish sperm). They are of two types—(1) simple globular and (2) simple fibrous proteins.

1. Simple globular proteins:

These proteins are soluble in one or more solvents and fall into two categories—

(a) Soluble in distilled water.

(b) Insoluble in distilled water.

(a) Soluble in distilled water:

They include following types—

They are readily soluble in water and can be precipitated from water by dilute acids and alkalies. Stronger or conc. acids and alkalies render albumins into soluble metaproteins. Upon heating, they get coagu­lated. Common examples are egg white albumin, serum albumin, legumelin (proteins of pulses), phaseolin (bean protein) and leucin (wheat protein).

(ii) Pseudoglobulins:

They are also soluble in water and can be precipitated from water by 1/4 to 3/4 saturation with an acid salt or am­monium sulphate. Unlike albumins they are rare in nature and include pseudoglobulin of milk whey. These are coagulated on heating.

These are basic proteins being highly soluble in water, dilute acids and dilute ammonium hydroxide solution. Upon mixing with mineral acids, they form crystalline salts and insoluble salts with more acidic proteins. They are not coagulated by heat and have low molecular weight. Examples are sperm proteins.

These are basic proteins having high molecular weight. They are insoluble in ammonium hydroxide but soluble in water and dilute mineral acids. They may occur in nucleoproteins.

(b) Insoluble in distilled water:

In it, are included following types—

They are soluble in dilute alkalies and acid but insoluble in distilled water, and neutral salt solutions and are present in cereal protein, e.g., glutenin (from wheat) and oryzenin (from rice).

(ii) Gliadins or Prolamins:

These proteins are also soluble in dilute alkalies and 60-80 percent alcohol. Prolamins occur in plants only and in­clude gliadin (wheat), hordein (barley) and zein (maize).

They are insoluble in water but get readily dissolved in dilute neutral salt solutions. Upon heating, they are coagulated and include vitellin (egg globulin), fibrinogen (blood protein), myosinogen (muscle protein), etc. Vegetable globulins comprise tuberin (potatoes), edestin (wheat) and legumin (wheat).

2. Simple fibrous proteins:

They are fiber-like in appearance and insoluble in cold water or cold reagent. They are found exclusively in animals and known as scleroproteins. Some forms of fibrous proteins are as follows—

They are indigestible proteins found in hair, feathers, nails, horns, etc.

These are insoluble proteins found in yellow elastic car­tilage, blood vessels, etc.

This is present in the silk.

These occur in white fibrous connective tissue namely tendons, matrix of bone and cartilage.

Above proteins, may be subdivided into two groups—

(i) Keratin-myosin-elastin-fibrinogen group and (ii) Collagen types. In the first category are included proteins of epidermis, hair, myosin of muscle fibres, and clotting proteins. Mammalian hair a-keratin forms β-keratin by action with alkali. X-ray analysis of the β-(or stretched) form of keratin-myosin-elastin-fibrinogen protein shows that atomic arrangements are not spiral but as a pleated ribbon polypeptide chain.

Collagen proteins are found in tendons, cartilage and upon hydrolysis form gelatin. A collagen molecule is asymmetrical, very long thin rodlet and consists of three peptide chains, each having proline, hydroxyproline and glycine.

B. Conjugated proteins:

These consist of simple proteins combined with a non-protein moiety, usually called as prosthetic group (if addition is organic) or cofactor (if addition is inorganic). For example, glycoproteins and mucopmteins contain carbohydrates and proteins in their molecules (e.g., mucin of saliva).

Lipoproteins contain amino acids and lipids in their molecules (e.g., lipovitellin of egg yolk, serum, protein of brain and nerve tissues). Nucleoproteins contain amino acids and nucleic acids in the molecules (e.g., nucleic acid proteins). Chromoproteins contain amino acids and pigments in their molecules (e.g., haemoglobin, haemocyanin, flavoproteins and cytochromes).

Haemoglobin and myoglobin contain the prosthetic group heme, an iron-containing organic compound that combines with oxygen. Phosphoproteins contain amino acids and phosphate groups in their molecules (e.g., casein), and metalloproteins contain amino acids and metallic ions in their molecules.

These consist of coagulated proteins and partly hydrolysed proteins, e.g., proteases, polypeptides.

2. Carbohydrates:

(L., carbo—coal: Gr., hydra—water). These are most common in protoplasm and are the main source of energy for all living beings. They are composed of С, H, and O. Hydrogen and oxygen are present in 2: 1 ratio as in water. When hydrolysed, they form glucose and water. The glucose is converted into glycogen as a storage product.

In May plants they form important constituents of cell walls and serve as supporting elements. Animal tissues have fewer carbohydrates the most important are glucose, galactose, glycogen and amino sugars and their polymers.

The principal carbohydrates found in protoplasm are of 3 kinds monosaccharides, oligosaccharides and polysaccharides. The first two, commonly known as sugars, are readily soluble in water. They can be crystallized and easily pass through dialyzing membranes. Polysaccharides neither crystallize nor pass through the membranes.

[I] Monosaccharides:

These are simple sugars having the empirical formula Cn (H20)n. They are classified and named according to the number of carbon atoms in their molecules—

These are characterized by the presence of 3 carbon atoms in their molecule such as glyceraldehyde and dihydroxyacetone.

They have four carbon atoms such as erythrulose.

These are sugars having five carbon atoms and form the main constituents of nucleic acids. In DNA, they occur as deoxyribose and in RNA, they are found as ribose. Ribose sugar is also found in some coenzymes like NAD, ATP and CoA.

These are compounds of six carbon atoms and include most common sugars such as glucose, fructose and galactose. They are sweet, readily soluble in water and easily crystallizable. In body, they form the primary source of energy and also as raw material for biosynthesis of complex carbohydrates.

It is also called grape sugar or dextrose and found in fruits, and in honey alongwith fructose. In water glucose exists in equilibrium be­tween α and β forms. It is main energy metabolite and all the carbohydrates taken in food are finally broken into glucose to start glycolysis and kreb’s cycle.

(b) Fructose (levulose):

It is also called fruit sugar or levulose and has similar composition to that of glucose but differs in properties. It is less readily digested or absorbed than glucose due to position of OH groups.

It is present in milk sugar or lactose along with glucose. Lactose gets decomposed to glucose and galactose after hydrolysis. It is readily absorbed like glucose.

Structurally, monosaccharides may be grouped into two categories—

(i) Aldoses having aldehyde group (H—C=0) at one end of the chain and CH2OH on the other hand.

(ii) Ketoses consisting of keto group (—C= O) at the second carbon atom.

These contain seven carbon atoms in thier molccules, e.g., sedoheptulose.

[II] Oligosaccharides:

These sugars are formed by the condensation of 2 to 6 molecules of monosaccharides called monomers. Likewise, on hydrolysis, they yield 2—6 molecules of monomers or simple sugars. Each monomer is linked with each other by the glycosidic linkages. On the basis of number of monomers, the oligosaccharides may be of following types—

These are formed by condensation of two molecules of monomers of monosaccharides with loss of one molecule of water. Their empirical formula is С12H22O11. Common examples are sucrose (formed by glucose and fructose), lactose (formed by galactose and glucose), and maltose (formed by two glucose monomers).

They contain three monomers, e.g., raffinose, rabinose, rhaminose, etc.

These contain four molecules of monosaccharides such as stachyose and scordose.

These have five monomers, e.g., verbascose.

[III] Polysaccharides:

These are complex sugars formed by the condensation of many molecules of monosaccharides with loss of equal number of water molecules. Their empirical formula is upon hydrolysis, they yield molecules of simple sugars which may further dissociate into monomers. Structurally, they are molecules of colloidal size having high molecular weights. They are of two kinds—

1. Homopolysaccharides:

These polysaccharides contain similar kinds of monomers in their molecules. Common homopolysaccharides are (i) starch, (ii) glycogen and (iii) cellulose.

It is the important storage food material of the plant cells occurring in their matrix as granules. Structurally, it comprises two long polymer molecules among which linear chain is of amylose, and amylopectin is branched.

It is contained mainly in animal liver cells and muscle fibres. It is readily soluble in water but forms colloidal suspension with protoplasm. Unlike starch, it is stored food in animal cells. Glycogen is composed of many molecules of glucose or it is polymer of glucose.

It is characteristic of plant cell walls where it provides mechanical support to the cells. Cellulose is a polymer of diasaccharide sugar-cellobiose (С12H22O11) which may contain many glucose molecules.

2. Heteropolysaccharides:

These are composed of different kinds of monosaccharide molecules. In their molecules, amino nitrogen sulphuric or phosphoric acids are common. Common heteropolysaccharides are as follows—

(a) Neutral heteropolysaccharides:

They are known as acetyl glucosamines and contain monosaccharides and acetylated amino nitrogen. Example is chitin which forms exoskeleton of insects, etc.

(b) Acidic heteropolysaccharides:

These polysaccharides contain different kinds of monosaccharides with sulphuric acid or phosophoric acid in their molecules. In it are included hyaluronic acid, heparin, chondroitin sulphate, etc. Heparin is an anticoagulant of blood found in liver, lung, thymus, blood.

Hyaluronic acid forms the cementing material of the connective tissues and occurs in the skin, connective tissues and synovial fluid of joints. Hyaluronic acid is hydrolyzed by hyaluronidase. Chondroitin sulphate is found in the cells of cartilage, cornea, umbilical cord and serves as a matrix for bone formation.

(c) Mucoproteins and Glycoproteins:

In it, molecules of proteins, monosaccharides and acetyl glucosamines unite to form characteristic mucoproteins and glycoproteins. Examples are gastric mucin, serum, albumin, blood group polysaccharides.

3. Lipids:

These (Gr., lipos—fats) are fats made of С, H and O. They are also colloids being insoluble in water but soluble in organic solvents like ether, chloroform, benzene, etc. This property of lipids and related compounds is the predominance of long aliphatic hydrocarbon chains or benzene rings. These structures are non-polar and hydrophobic.

In many lipids these chains may be attached at one end to a polar group which make it capable of binding water by hydrogen bonds. Lipids are important constituents of the cell membranes, vitamins and hormones of the cells. These are present as storage products supplying energy. They are of several types—

[I] Simple lipids:

These are neutral fats, composed of fatty acids and glycerol as triglycerides. These glycerides may be either oils or fats. They include tallow and lard oils—cod liver and castor oil. On hydrolysis they yield one molecule of glycerol and 3 molecules of fatty acids. Neutral fats accumulate in adipose tissue.

The fatty acids may be saturated (e.g., palmitic, stearic acids) or unsaturated such as oleic, linoleic, linolenic acids, etc. The animal cells contain palmitic, stearic, palmitoleic, oleic, linoleic and linolenic acids. The simple lipids of the cell cytoplasm are neutral fats which are found in plant and animal cells as stored food substances, and waxes which are the esters of fatty acids of high molecular weight with the alcohols other than glycerol (e.g., bees wax).

Waxes have a higher melting point than the neutral fats. For example, bees wax is composed primarily of palmitic acid esterified with either hexacosonol or triacontanol. Waxes are chemically inert and form protective covering at numerous locations in cells.

Fatty acids always have an even number of carbons. For example palmitic acid has 16 carbons and stearic acid has 18 carbons. Sometimes the hydrocarbon chain has double bonds (—С = С—), and in this case the fatty acid is said to be non-saturated, for example, oleic acid has 18 carbons and one double (unsaturated) bond.

The carboxyl groups of fatty acids react with the alcohol groups of glycerol in the following way—

The resulting triglycerides are used by organisms to store spare energy. They liberate large amounts of energy, i.e., about twice than the carbohydrates and proteins, since their oxidation is very slow. After oxidation they form CO2 and water.

[II] Complex lipids:

These compound lipids contain fatty acids, alcohol along with other specific compounds like phosphorus, amino nitrogen, nerrone etc. Upon hydrolysis these lipids yield other compounds in addition to alcohol and acids. They serve as structural components of the cell, particularly in cell membranes. They may be of following types—

1. Phospholipids (Phosphatides):

They are the diesters of phosphoric acids and contain in their molecules glycerol, fatty acids, and phosphoric acids. Phospholipids are the main components of unit membranes of the cells and regulate cell permeability, blood coagulation, transport and dietary fat metabolism.

A phospholipid has only two fatty acids attached to the glycerol molecule. The third hydroxyl group of glycerol is esterified to phosphoric acid instead of to a fatty acid. This phosphate is also bound to a second alcohol molecule, which can be choline, ethanolamine, inositol or serine depending on the type of phospholipid. They are subdivided into fol­lowing categories—

In it, phospholipids are united with a nitrogenous base— choline and thus are also called phosphatidyl choline. These are monoamino-mono-phospholipids containing glycerol, fatty acids, phos­phoric acid and choline. In nervous tissue, phospholipids occur along with cholesterol. Fatty acids found in lecithin’s include palmitic acid, stearic, acid, oleic acid, arachidonic acid and linoleic acid. Usually, only two fatty acids occur in one lecithin molecule.

Lecithin’s are unstable due to presence of unsaturated fatty acids and undergo oxidation or hydrogenation. They play important role in metabo­lism of fat, permeability, osmotic tension, desaturation of fats and other metabolic processes.

They comprise phosphatidyl ethanolamine and phosphatidyl serine. In other words, choline group of lecithin’s is replaced by an amino ethanol group (P-amino-ethanol or serine). Cephalins form components of certain lipoproteins and play important part in blood coagulation.

In these phospholipids, there occurs a enroll form of long chain aldehyde connected by ester linkage. Plasmalogens are similar to lecithin’s but one of the fatty acids is replaced.

(d) Sphingolipids:

These are found mostly in the cells of brain. In them, instead of glycerol, there occurs amino alcohol, called sphingol or sphingosine. Myelin sheath of the nerve fibres contains lipid—sphingomyelin formed of sphingosine and phospholipids. Sphingolipids are also called sphingomyelins.

They are similar to sphingolipids but contain carbohydrate radicals along with nitrogen and fatty acids. Matrix of animal cells consists of two kinds of glycolipids namely cerebrosides and gangliosides.

They contain sphingosine, fatty acids and galactose or glucose in their molecules and are characteristic of white matter of brain cells and myelin sheath. Common cerebrosides are kerasin, cerebron, nervon, oxynervons and phrenosin.

These are also complex molecules being composed of sphingosine, fatty acids and one or more molecules of glucose, lactose, galactosamine and neuraminic acid. They are found in the grey matter of the brain, membrane of erythrocytes and spleen cells.

Sulfa tides contain sulphuric acid esterified to galactose.

These contain proteins and lipids in their molecules and are found in the blood of mammals. In it cholesterol and globulin protein are specific.

[III] Derived lipids:

Upon hydrolysis, derived lipids yield simple and complex lipids along with other substance such as fatty aldehydes, hydrocarbons, sterids, ketones, alcohols, etc. They are of the following types-

These are wax-like lipids found in Free State as well as forming fatty acid esters. They are characterised by the presence of ring-structure in their molecule. Sterids fall into two categories namely steroids and sterols.

These are more complicated lipids containing an aliphatic ring nucleus of saturated hydrocarbons. In other words, these are aromatic alcohols having OH groups. The cyclic ring is cyclopentano perhydro-phenanthrene. In plant cells, there occurs a peculiar sterol—β-sitosterol, and in fungi, ergosterol (one of provitamins D). They include sex hormones, vitamin D and bile acids.

Steroids which possess hydroxyl (OH) group in their molecules are called as sterols. Sterols occur in animal and plant oils and fats. Examples are ergosterol from yeast, cholesterol from animals and ergosterol, stigmasterol from plants. They are wax-like solid alcohols found in most living cells.

[IV] Carotenoids:

Thses are red or orange pigments in cells being insoluble in water but soluble in organic solvents (e.g., vitamin-A-carotene). Their general formula is C40H56. There are about seventy carotenoids found in plant and animal cells. Among them are included carotenes, xanthophylls, retinene, lactoflavin in milk, riboflavin (vitamin B2), xanthocyanins, coenzyme, anthocyanins, flavones, flavonols, flavonones, etc.

Carotenes are α, β and γ types among P carotenes synthesize vitamin A. Xanthophylls have С, H and О as lutein, yellow leaves pigment. Chemically carotenoids are porphyrins (Gr. porphyra— purple). Porphyrins linked with metals and proteins form the important pigments of animal and plant cells (e.g., chlorophyll and haemoglobin).

4. Enzymes:

[I] Structure of enzymes:

These are complex proteins found in the protoplasm of colloidal nature. These enzymes act as biocatalyzers (biological catalysts) in various metabolic processes and thus hasten the process.

A catalyst is a substance that accelerates chemical reactions but that is not itself modified in the process, so that it can be used again and again. Enzymes are the largest and most specialized class of protein molecules. More than thousand different enzymes have been identified.

Many of them have been obtained in pure, and even crystalline condition. Enzymes rep­resent one of the most important products of the genes obtained in the DNA molecule. The enzymes may be intracellular (i.e., acting inside the cells) or extracellular (i.e., reacting in external medium). Enzymes are sub- state specific, i.e., a particular enzyme will act only on a certain substrate.

Some enzymes have nearly absolute specificity for a given substrate and will not act on even very closely related molecules, as for example, stereoisomers of the same molecule. Other enzymes have relative specificity, since they will not act upon a variety of related compounds.

Some enzymes require small non-protein components called cofactors for their activity. For example, some enzymes are conjugated proteins having tightly bound prosthetic groups, as in the case of the cytochromes, which have an iron porphyrin complex. Iron atoms are essential in many electron—transfer reactions.

Other enzymes can not function without the addition of small molecules called coenzymes, which become bound during the reaction. When joined with a coenzyme, these inactive enzymes, also called apoenzymes, form active holoenzymes.

For example, dehydrogenases utilise either nicotinamide—adenine dinucleotide (NAD + ) or nicotinamide— adenine dinucleotide phosphate (NADP + ). These are among the most important coenzymes. The function of the coenzyme is to accept two electrons and a hydrogen ion from the substrate, thus oxidizing it —

Substrate + NAD + + Enzyme → Oxidized substrate + NADH + H +

The two electrons of NADH can then be transferred to a second molecule, which will become reduced, i.e., it gains electrons.

In the cell the energy-producing catabolic enzymes use NAD as coenzymes in the synthetic processes, however, use NADPH as a hydrogen donor. In many coenzymes, as in NAD + and NADP + containing nicotinamide, the essential components are vitamins of В group. Enzymes are unstable substances which can be destroyed by higher temperature.

Generally these remain in inactive state and are activated by other substances. For example trypsinogen, an inactive enzyme, is activated by enterokinase enzyme in intestine to active trypsin.

Trypsinogen (inactive) enterokinase →Trypsin (active)

[II] Classification of enzymes:

The enzymes have been classified into six categories according to recent terminology as described by De Robertis (1971). They are—

(1) Oxidoreductases, performing oxidation—reduction reactions of the cells e.g., hydrogenases (reductases), oxidases, oxygenases and peroxidases.

(2) Transferases, which cause the transfer of groups.

(3) Hydrolases, which hydrolyze the reaction.

(4) Lysases, causing addition or removal of the groups to or from double bonds.

(5) Isomerases, which catalyze isomerizations, and

(6) Ligases or synthetases, which condense two molecules by splitting a phosphate bond. Besides, there are isoenzymes having similar action but different structural configuration. These isoenzymes are produced by genetic changes. These have a relation with the heredity (Latner and Skillen, 1969, and Weyer, 1968). There are about 100 isoenzymes in the cell.

[III] Mode of enzyme action:

According to the present concept of enzymic activity, enzyme and substrate (substance on which enzyme acts) form lock and key relationship. In it, substrate attaches itself to the protein component of the enzyme, called active site.

This site of enzyme is directly related to the primary (sometimes secondary and tertiary) structure of protein because it concerns to a special amino acid sequence. More recently, a new concept called induced-fit has been postulated by Koshland (1960) and Yankeelov (1965).

Active site is not a rigid structure. In some enzymes the active site is precisely complementary to the substrate only after the substrate is bound, a phenomenon called induced-fit. The binding of the substrate induces a conformational change in the protein and only then the chemical group’s essential for catalysis will come in close contact with the substrate.

The binding of the substrate to the active site involves forces of a non-covalent nature, which are of very short range. This explains why the enzyme—substrate complex can be formed only if the enzyme has a site that is exactly complementary to the shape of the substrate.

The existence of an enzyme-substrate complex (ES) at the active site was postulated by Michaelis and Menten (1913) on the basis of kinetic evidence.

The enzyme-substrate reaction proceeds in two steps:

(1) The first step is as follows.

Enzyme + Substrate → Enzyme- Substrate Complex (ES)

(2) In the second step the (ES) complex breaks down to form the product and the free enzyme, which will now be available for processing a new substrate molecule.

K1, K2, K3, andK4, are rate constants for the reaction. All steps are reversible, but in general K4 is negligible and the follows—

As is evident the velocity of the enzyme reaction depends on the con­centration of substrate.

At low substrate concentrations, the initial velocity increases rapidly. Here the amount of product formed is proportional to the substrate con­centration, (S). However, as the substrate increases, the reaction saturates and reaches a point of equilibrium in which the velocity no longer depends on (S). At this point, because of the great excess of substrate, all the en­zyme is in the form of an (ES) complex, and the maximum velocity of the reaction is reached.

Some enzymes require small non-protein components called cofactors for their activity. These compounds are bound to the protein. Cofactor is also termed prosthetic group which is bound very tightly by covalent linkages to the enzyme protein. Such enzymes are called coenzymes. Many enzymes require metal ions for full activity, e.g., Mg ++ and Mn ++ .

The protein portion of an enzyme is called apoenzyme and the complete enzyme is often called the holoenzyme. Nicotinamide—adenine dinucleotide (NAD) or nicotinamide—adenine dinucleotide phosphate (NADP) are the important coenzymes.

The function of the coenzyme is to accept two electrons and a hydrogen ion from the substrate, thus oxidizing it. In many coenzymes (as in NAD and NADP), the essential components are vitamins, particularly those of the В group.

Isoenzymes are multiple forms of an enzyme which differ by minor varia­tions in amino acid composition and sometimes in regulation. For example, lactic dehydrogenase (LDH), which catalyzes the conversion of pyruvate to lactate.

5. Regulatory Substances:

These are also complex organic secretions which maintain the metabolic rate of cells in an orderly manner. These include hormones and vitamins.

[I] Hormones:

Hormones are secretions of the protoplasm of endocrine cells which constitute the ductless glands. These are produced in very small quantities and are poured into blood which carries them to organs of need.

The hormones present in the cytoplasm of the cells regulate the synthesis of m-RNA, enzymes and various other intracellular physiological activities. These are produced by different glands. Pituitary gland, which is usually called the ‘master gland of endocrine orchestra, secretes about a dozen of hormones.

Among these, somatotrophic affects growth pituitary affects the mammary glands, vasopressin for pressure of blood vessel, gonadotrophic for control of gonads, thyrotrophic for control of thyroid gland. Thus, it controls every part of the body.

Other hormones are thyroxin secreted by thyroid glands giving energy cortin secreted by adrenal cortex maintaining balance of salts in blood, etc., and adrenalin secreted by adrenal medulla is effective in involuntary muscles.

Gonadial hormones may be either androgens or estrogens, which control the development of sex organs and secondary sexual characters. In insects, the hormone ecdysone has been found to form Balbiani rings in the giant chromosomes. It also controls the moulting and metamorphosis in insects (Beermann, 1965).

[II] Vitamins:

Vitamins as a matter of fact are not present in the cytoplasm but are obtained by the cell from its environment along with food, etc. They are essential for normal growth, metabolism and maintenance of vigour. Deficiency of vitamins reduces the rate of cellular metabolism and may result in a deficiency disease. These vitamins may be of many types, some important ones are the following—

It resists the living being to infection and forms visual purple in retina. Its deficiency causes night blindness in man. It is present in carotene.

2. Vitamin В (Complex):

It is made of several vitamins like vitamin В1, В6, B12, etc. Vitamin B1 is essential for proper metabolism of carbohydrates and tissue respiration. Its deficiency causes beriberi disease (nervous disease). Vitamin B2 is also essential for growth. Vitamin В6 is essential for protein synthesis and causes anemia. Vitamin В12 is helpful for R.B.C. formation in man.

It is water soluble, found in tomatoes, etc., and is useful in tissue respiration, normal growth of bones and teeth. Its deficiency results in scurvy in which bones become weak and skin becomes rough.

It is fat soluble and is essential for the absorption of calcium and phosphorus, thus helps in bone formation. Its deficiency causes dental carries and deformation of bones.

It is essential for rapid cell growth and its deficiency causes death of embryo and sterility.

It helps in the formation of blood protein prothrombin and its deficiency causes hemorrhage as blood fails to coagulate.

It is a mixture of eriodictin, hesperidin and rutin, and maintains cement of capillary walls, thus affecting capillary fragility.

6. Nucleic Acids:

These are important organic substances found in nucleus and cytoplasm. They control the important biosynthetic activities of the cell and carry hereditary information from generation to generation. Thus, nucleic acids are macromolecules of the utmost biological importance.

They are associated with the chromosomes and transmit various information to cytoplasm. These nucleic acids are two types: (i) deoxyribonucleic acid (DNA) and (ii) ribonucleic acid (RNA). DNA is the major store of genetic information. This information is transmitted by transcription into RNA molecules, which are utilized in the synthesis of proteins.

In higher cells DNA is localized mainly in the nucleus as part of the chromosomes. A small amount of DNA is present in the cytoplasm contained within mitochondria and chloroplasts. RNA is found both in the nucleus, where it is synthesized, and in the cytoplasm, where the synthesis of proteins takes place. Both types of nucleic acids are the polymers of the nucleotides. A nucleotide is made of nucleoside and phosphoric acid.

The nucleoside is formed of the pentose sugars (ribose or deoxyribose) and nitrogen bases (purines and pyrimidines). The purines are adenine and guanine, and the pyrimidines are the cytosine, thymine and uracil. The cytoplasm contains only RNA, and DNA is exclusively found in nucleus. After a mild hydrolysis the nucleic acids are decomposed into nucleotides.


Hormones: Biology Notes on Hormones

Here is a compilation of notes on hormones. After reading these notes you will learn about: 1. Meaning of Hormones 2. Characteristics of Hormones 3. Classification 4. Synthesis 5. Transport and Metabolism 6. Patterns of Secretion 7. Control of Secretion 8. General Functions 9. General Mechanisms.

  1. Notes on the Meaning of Hormones
  2. Notes on the Characteristics of Hormones
  3. Notes on the Classification of Hormones
  4. Notes on the Synthesis of Hormones
  5. Notes on the Transport and Metabolism of Hormones
  6. Notes on the Patterns of Hormone Secretion
  7. Notes on the Control of Hormone Secretion
  8. Notes on the General Functions of Hormones
  9. Notes on the General Mechanisms of Hormones

Note # 1. Meaning of Hormones:

Hormones are any substances released by a cell or gland which act through receptors on another cell near or far regardless of the singularity or ubiquity of the source and regardless of the means of conveyance – blood stream, axoplasmic flow, or immediate inter­cellular space.

Insulin, estrogen, gastrin etc.

Note # 2. Characteristics of Hormones:

Following criteria are considered while characterizing hormones in general.

1. Chemical nature of hormones:

Chemically, hormones may be grouped into three general categories:

This category comprises of hormones that are derived from single amino acid. For example, thyroid hormones derived from iodinated amino acid, tyrosine, and norepinephrine, epinephrine, dopamine are derived from the amino acid tyrosine.

(b) Proteins and peptides:

These hor­mones are protein in nature. The individual hormone could be referred to as peptide, polypeptide or protein in nature, depending on their specific chain length. For example, thyrotropin releasing hormone (TRH) is com­posed of only 3 amino acids (small peptide), while pituitary gonadotropins possess as many as 180 amino acids (large peptides).

These hormones are derivatives of cholesterol. For example, adrenal and gonadal steroids have intact steroid nucleus, while vitamin D has broken steroid nucleus. Besides the above hormones, prosta­glandins, prostacyclins, leukotrienes, which are related to hormones, are derived from fatty acids.

Note # 3. Classification of Hormones:

Hormones may be classified variously. Hormones in broader sense refer a number of substances that have already been defined. Here types of hormones accor­ding to their chemical nature will be discussed. Hormones are derived from major classes of compounds that are used for general function within the body.

Thus, they are either proteins or derived proteins or amino acid analogues or lipids. When the structure of a hormone is known it is referred to as such but when their activities have been isolated but structures are not known, they are referred to as factors.

According to the chemical origin hormones may be of following types:

Peptide hormones are com­posed of amino acids, the number of which may be as few as 3 amino acids (e.g. thyro­tropin releasing hormane or TRH) to as many as 180 or more (e.g. pituitary gonadotropins). However, individual hormone may be referred to as peptide (with small number of amino acids), polypeptide or protein (with single or more long chains of amino acids.) in nature depending on their specific chain length.

The amino acid chain may be linear as found in α-MSH or may be ring like as found in neuro-hypophyseal hormones (oxytocin and vasopressin). Some hormones may have more than one chain, such as insulin which has two polypeptide chains.

All peptide hormones are direct translation products of specific mRNA, but may be cleavage products of larger pre­cursor (e.g. insulin) proteins, or modified pep­tides (e.g. FSH, TSH are glycoproteins).

Thyroid gland secretes two hormones the triiodothyronine or T3 and tetraiodothyronine or T4. These hormones are derivatives of amino acids. They are derived from the amino acid tyro­sine with which an inorganic ion, (i.e., iodine) is incorporated. These hormones are indispensable for normal growth and development.

Steroid hormones are derived from cholesterol which, in turn, is produced either by de novo synthesis or by uptake of low density lipids (LDL) through LDL receptors. Steroid hormones are pro­duced in the adrenals, ovaries, testes, placen­ta and to some extent in peripheral tissues. The overall pathways in these organs are similar, though difference in the specific enzymes present in the various cells generates different final products.

In animal the vitamin D3 (cholecalciferol) acts as the precursor of the active vitamin D3 or Calcitriol (or 1α, 25-di-hydroxycholecalciferol) which behaves as hormone. It acts via binding to a soluble calcitriol receptor protein belonging to the steroid T3-retinoid receptor superfamily. This hormone mainly regulates calcium and phos­phate metabolism.

Catechol-amines are synthesised from the amino acid tyrosine and then stored in granules analogous to those that secrete polypeptide hormones. Two important catechol-amines are epinephrine and norepinephrine which are synthesised mainly by adrenal medulla. Dopamine is another catecholamine. Catechol-amines also act as neurotransmitter.

Eicosanoids are hormone-related substances that are derived from fatty acids. Common examples of this hormone include prostaglandins, prostacyclins and leukotriene. The arachidonic acid is the most important and abundant precursor of the various eicosanoids in humans.

Arachidonic acid in turn is formed from the essential fatty acid linoleic acid. Eicosanoids play signi­ficant roles in many physiological processes (Fig. 7.10).

Note # 4. Synthesis of Hormones:

Like all other proteins, peptide and protein hormones are synthesised in the rough endoplasmic reticulum. Their amino acid sequences are determined by specific mRNA having defi­nite nucleotide sequences dictated by speci­fic gene. Translation of such mRNA results in the ribosomal synthesis of a protein, usually larger than the mature hormone.

This precur­sor is referred to as pro-hormone or preprohormone. The pro-hormone is extended at their amino termini by a hydrophobic amino acid sequence called leader or signal pep­tide. Preprohormones in addition to signal peptides, also contain internal cleavage sites that yield different bioactive peptides upon enzymatic action.

With the aid of hydrophobic leader pep­tide, the hormone precursors move across the ER membrane to be transported to Golgi complex. The leader sequence is removed before the synthesis of polypeptide chain has ended and this permits the protein to gain its secondary structure during its transport to Golgi.

Following its arrival at Golgi the pro­-hormones may be processed by proteolytic enzyme to generate mature hormones, and /or by other enzymes that add non­protein residues such as carbohydrates in case of glycoprotein hormones (e.g., FSFI, LH).

Whatever the case, the hormone stored in vesicles will fuse the cell membrane dur­ing their release and their contents will be extruded into the extracellular perivascular space. This process is called exocytosis, which is the most common process of hor­mone release.

The synthesis of amine and steroid hor­mones are different from that of peptide hormones. Amine and steroid hormones originate from the precursor molecule tyro­sine and cholesterol, respectively.

Within the cells of synthesis, these precursor molecules are subjected to the sequential action of sev­eral enzymatic catalysis resulting in the formation of various intermediate products that themselves may be hormones. In con­trast to peptide hormones, thyroid hormone and steroids, once produced, can freely cross the cell membrane without having to be packed in granules and are actively exocytosed.

There are ample examples of hormones that are produced at sites other than those in which their precursor is formed. In some cases, a hormone with less activity is con­verted into an active form by the action of enzymes in the circulation or other tissues.

3. Delivery of hormones:

Hormones (in broader sense) may be delivered from the site of synthesis to their target organ or cell by one of several ways:

(i) Endocrine, when the hormones are released into circulation directly

(ii) Paracrine, when the released hormones diffuse to its adjacent target cells through immediate extracellular space

(iii) Autocrine, when following release, the hormone is feed backed on the cell of origin

(iv) Neuroendocrine, when the hormone released by a nerve is blood borne

(v) Neurocrine, when a neuron releases its hormone into a synaptic cleft between two adjacent cells,

(vi) Luminal, when a hormone is released into the lumen of the gut.

Note # 5. Transport and Metabolism of Hor­mones:

Following the release to outside from site of synthesis, hormones may circu­late freely into the bloodstream or it may be bound to a carrier protein. In general, amines, peptides and protein hormones circulate in free form, whereas, steroids and thyroid hormones are bound to transport proteins (carrier proteins).

An exception to this rule is provided by insulin-like growth factors which despite being polypeptide, circulate tightly attached to specific proteins. Most common carrier proteins include thy­roid hormone-binding globulin (TBG) that carry thyroid hormone, testosterone-binding globulin (TeBG) and cortisol-binding globu­lin (CBG) that carry testosterone and Cortisol, respectively.

Hormones, either initiate immediate target tissue responses or set in motion more long-term effects. In either cases, hormones must be continuously inactivated or the cellular response would be continuously acti­vated. The metabolic clearance rate (MCR) of a hormone defines quantitatively its removal from plasma.

Under steady state conditions, the MCR represents the volume of plasma cleared of the hormone per unit of time. The plasma half-life of a hormone is inversely related to MCR (Table 7.3). Only a little portion of circulating hormones is removed from the circulation by most target tissues.

The bulk of hormone clearance is done by the liver and the kidneys where a number of enzymatic degradations occur that include hydrolysis, oxidation, hydroxylation, methylation, decarboxylation, sulfation and glucoronidation. In general, only a small fraction (<1%) of any hormone is excreted as such through urine or feces.

Note # 6. Patterns of Hormone Secretion:

The basal secretion of most hormones is not a con­tinuous process but rather has a pulsatile nature. The pulsatile pattern of hormone secretion is characterised by episodes of release that can be as frequent as every 5-10 minutes each episode is followed by a quies­cent period during which plasma levels of hormone fall toward basal values.

Another discharge then occurs and the cycle repeats itself, often varying in both amplitude and fre­quency of the pulses. In the case of hormones subjected to negative feedback control, removal of the inhibitory feedback signal results in a marked enhancement of the ampli­tude and frequency of episodes of secretion.

Most prominent episodes of release may occur with a frequency of about an hour, this mode of release is called circhoral when episodes of release occur at intervals longer than an hour but less than 24 hours, the rhythm is called ultradian if the periodicity is of about a day, the rhythm is called circadian and if it occurs every day it is called quotidian or diurnal (e.g. ACTH).

Some hor­mones may have a much less periodicity. For example, the monthly pre-ovulatory discharge of gonadotropins recurs about every 30 days, a pattern of release known as circatrigintan. Thyroxine exhibits changes in plasma levels that occur over months. If the changes take place on a yearly basis, the rhythm is called circannual or seasonal.

Note # 7. Control of Hormone Secretion:

Nerve impulses control some endocrine secretions. For exam­ple, during stress and emotion, splanchnic nerve stimulates the synthesis and release of catecholamines from adrenal medulla. Nerve impulses from hypothalamic osmoreceptors evoke secretion of vasopressin from neuro­-hypophyseal axon-terminals. Impulses from brain, hippocampus, amygdala and other limbic system areas may cause release of acetylcholine and biogenic amines at their axon-terminals that in turn, regulate the release of different hypo-physiotropic hor­mones such as GHRH, CRH, and TRH from hypothalamus.

Hormones often regulate hormone secretion from other endocrine glands. For example, secretion of adrenocortical, gonadal and thyroid hor­mones are stimulated respectively by cortico­tropin (ACTH), gonadotropins (GTH) and thyrotropin (TSH), which are as such tropic hormones of anterior pituitary that in turn are regulated by hypothalamic hypo-physio­tropic hormones such as CRH, GnRH and TRH, respectively.

(iii) Feedback controls:

The secretion of a hormone may be stimulated or inhibited by the feedback effect of some other hormone or metabolites.

1. Negative feed-back control:

A high blood level of a hormone may inhibit the secretion of that hormone. It is shown by tar­get gland hormones that inhibit the secretion of their tropic hormones. For example, high levels of Cortisol from adrenal cortex may inhibit the secretion of pituitary-corticotropin release and corticotropin-releasing hormone (CRH) from hypothalamus through long-loop feedback, all these lead to decline in Cortisol secretion itself.

High levels of tro­pic hormones sometimes inhibit the secretion of corresponding releasing factor from hypothalamus through short-loop feedback (Fig. 7.1). Sometimes, blood level of some ions or metabolites also shows feedback con­trol over hormone release. For example, a rise in serum Ca 2+ causes rectilinear fall in para­thyroid hormone rise in blood glucose cau­ses a decline in glucagon secretion.

2. Positive feedback control:

Hormone- secretion may be stimulated by a positive feedback effect of another hormone or ion or metabolite. For example, sharp pre-ovulatory rise in LH secretion from anterior pituitary occurs in response to high blood level of estradiol elevated serum calcium level cau­ses stimulation of calcitonin release from thyroid gland.

Furthermore, some hormones may exert a negative feedback on the cells within which they are synthesised by a so-called auto-inhibition (For control of specific hormones, see different endocrine glands).

Note # 8. General Functions of Hormones:

Hormones control the activity of almost all cells in the body. However, their functions, in general, may be exerted in four broad physiological areas. These are growth and development, reproduction, maintenance of internal environment, and regulation of energy balance:

1. Growth and Development:

Many hormones exert primary and permissive roles in timing and progression of growth, both for overall body and for individual tissue. Classical examples of growth regu­lating hormones include GH, thyroid hor­mones, glucocorticoids, androgens and estro­gens. The stimulatory effect of GH only on body growth is mediated by a group of peptides called insulin-like growth factors (IGFs).

Again, in absence of thyroxine, GH fails to stimulate skeletal growth, a pheno­menon that appears to be regulated to a reduced ability of the tissue to respond to IGFs. Hormones also play a regulatory role in the earliest aspects of cell division and differentiation of the fertilised eggs.

Most aspects of reproduction including growth and structural integrity of reproductive organs, production of gametes, patterns of sexual behaviour, sexual differences etc., are controlled by the interaction of hormones produced by gonads, anterior pituitary (GTH) and growth hor­mone, Estrogens in females and testosterone in males play fundamental roles in the deve­lopment of primary and secondary sexual organs.

Ovulation in females and spermatogenesis in males are processes that are tightly controlled by the pituitary gonadotropins (LH and FSH), which act either directly on the gonads to promote follicular development (ovary) and formation of sperm (testis) or indirectly through their stimulatory effects on estrogen and testosterone secretion.

3. Maintenance of Internal Environ­ment:

Homeostasis in internal environment is maintained through the control of extra­cellular fluid volume and blood pressure, electrolyte composition of body fluid, regu­lation of plasma and tissue levels of calcium and phosphate ions, and the maintenance of bone, muscle and body stores of fats.

A num­ber of hormones regulate these processes e.g. vasopressin, aldosterone regulate the elec­trolyte and water balance, thus, in turn, regu­late blood pressure and extracellular fluid volume.

Plasma levels of calcium and phosphate are controlled by parathyroid hormone (PTH), 1, 25-di-hydroxy-vitamin D3 and calci­tonin. The general functions of bone, muscle and adipose tissue are regulated by hormones as diverse as PTH, estrogens, androgens, GH, catechol-amines, insulin, glucagon and gluco­corticoids.

4. Regulation of Energy Balance:

For an organism to survive, maintenance of ener­gy homeostasis requires a balance between food consumption and energy expenditure. The hypothalamus plays a central role in this process by integrating a variety of afferent sensory, visual, biochemical, and hormonal signals reflecting the nutritional status of the organism.

All these signals are processed to activate efferent signals that regulate both feeding behaviour and energy expenditure. Energy expenditure in turn, is regulated via mechanisms controlling the metabolic rate, such as those influenced by the sympathetic and parasympathetic nervous systems and by insulin, glucagon and thyroid hormones.

Recent identification of the peptide leptin as a hormone produced by white adipose tissue reveals that it acts on brain (as lipostat or adipostat) to decrease food intake and increase energy expenditure. Like leptin, three other peptides – MC4-R, urocortin and bombesin receptor type-3 are known to sup­press feeding behaviour.

On the other hand, two novel neuropeptides termed as orexin A and B were identified to stimulate feeding behaviour. All such factors control the energy homeostasis of an organism.

Note # 9. General Mechanisms of Hormone Action:

Higher mammals including human pro­duce more than 100 different hormones, each of which is capable of interacting with one or more types of cell distributed in tissues throughout the body. The question is what mechanism or characteristic of a cell deter­mines whether it will be responsive to a particular hormone.

The major factor deter­mining the tissue response to a hormone was found to be due to some molecular compo­nents of a cell, the so-called receptors. Hormone receptors are proteins occurring in the plasma membrane, nuclear or extra- nuclear sites such as endoplasmic reticulum or cytosol that possess a hormone-binding site and a signal transducer or DNA- binding site.

Receptor provides the means by which hormones initially interact with cells.

Each receptor serves two critical func­tions:

1. Recognition of the hormone as an entity distinct from all of the other sub­stances present in blood or extracellular fluid, and

2. Transformation of the binding interaction into a signal that modifies cellu­lar metabolism and/or growth.

Each cell type of an organism does not possess receptors for all hormones, but rather only a limited number of receptor types. Some hormones stimulate a number of tissues, which implies that each of the diverse tissue possesses receptors for those hormones, for examples, insulin stimulates glucose uptake by hepatocytes, fat cells and some muscle cells, and interact with many other cell types.

When more than one tissue responds to a particular hormone at one time, it might be expected that all different physio­logical responses would complement the physiological process being regulated. At normal physiological levels, each hormone interacts with its own specific cellular recep­tor.

For example, estradiol interacts with estro­gen receptors, not with other steroid recep­tors. Thus, hormone receptors possess a recog­nition function that then must be converted into the hormone’s biological functions.


References

Allen, G. W., Liu, J., Kirby, M. A., and De Leon, M. (2001). Induction and axonal localization of epithelial/epidermal fatty acid-binding protein in retinal ganglion cells are associated with axon development and regeneration. J. Neurosci. Res. 66, 396�. doi: 10.1002/jnr.1232

Anbalagan, M., Huderson, B., Murphy, L., and Rowan, B. G. (2012). Post-translational modifications of nuclear receptors and human disease. Nucl. Recept. Signal. 10:e001. doi: 10.1621/nrs.10001

Ang, Z., Xiong, D., Wu, M., and Ding, J. L. (2018). FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing. FASEB J. 32, 289�. doi: 10.1096/fj.201700252RR

Arai, Y., Funatsu, N., Numayama-Tsuruta, K., Nomura, T., Nakamura, S., and Osumi, N. (2005). Role of Fabp7, a downstream gene of Pax6, in the maintenance of neuroepithelial cells during early embryonic development of the rat cortex. J. Neurosci. 25, 9752�. doi: 10.1523/JNEUROSCI.2512-05.2005

Arai, Y., Sampaio, J. L., Wilsch-Brauninger, M., Ettinger, A. W., Haffner, C., and Huttner, W. B. (2015). Lipidome of midbody released from neural stem and progenitor cells during mammalian cortical neurogenesis. Front. Cell. Neurosci. 9:325. doi: 10.3389/fncel.2015.00325

Audet, M., and Stevens, R. C. (2019). Emerging structural biology of lipid G protein-coupled receptors. Protein Sci. 28, 292�. doi: 10.1002/pro.3509

Bae, I.-S., Park, P. J., Lee, J. H., Cho, E.-G., Lee, T. R., and Kim, S. H. (2017). PPARgamma-mediated G-protein coupled receptor 120 signaling pathway promotes transcriptional activation of miR-143 in adipocytes. Gene 626, 64�. doi: 10.1016/j.gene.2017.05.016

Bahar Halpern, K., Veprik, A., Rubins, N., Naaman, O., and Walker, M. D. (2012). GPR41 gene expression is mediated by internal ribosome entry site (IRES)-dependent translation of bicistronic mRNA encoding GPR40 and GPR41 proteins. J. Biol. Chem. 287, 20154�. doi: 10.1074/jbc.M112.358887

Balendiran, G. K., Schnutgen, F., Scapin, G., Borchers, T., Xhong, N., Lim, K., et al. (2000). Crystal structure and thermodynamic analysis of human brain fatty acid-binding protein. J. Biol. Chem. 275, 27045�. doi: 10.1074/jbc.M003001200

Banaszak, L., Winter, N., Xu, Z. H., Bernlohr, D. A., Cowan, S., and Jones, T. A. (1994). Lipid-binding proteins - a family of fatty-acid and retinoid transport proteins. Adv. Protein Chem. 45, 89�. doi: 10.1016/S0065-3233(08)60639-7

Benedict, C., and Grillo, C. A. (2018). Insulin resistance as a therapeutic target in the treatment of Alzheimer’s disease: a state-of-the-art review. Front. Neurosci. 12:215. doi: 10.3389/fnins.2018.00215

Bennaars-Eiden, A., Higgins, L., Hertzel, A. V., Kapphahn, R. J., Ferrington, D. A., and Bernlohr, D. A. (2002). Covalent modification of epithelial fatty acid-binding protein by 4-hydroxynonenal in vitro and in vivo. Evidence for a role in antioxidant biology. J. Biol. Chem. 277, 50693�. doi: 10.1074/jbc.M209493200

Bernardo, A., Bianchi, D., Magnaghi, V., and Minghetti, L. (2009). Peroxisome proliferator-activated receptor-gamma agonists promote differentiation and antioxidant defenses of oligodendrocyte progenitor cells. J. Neuropathol. Exp. Neurol. 68, 797�. doi: 10.1097/NEN.0b013e3181aba2c1

Bernardo, A., Giammarco, M. L., De Nuccio, C., Ajmone-Cat, M. A., Visentin, S., De Simone, R., et al. (2017). Docosahexaenoic acid promotes oligodendrocyte differentiation via PPAR-gamma signalling and prevents tumor necrosis factor-alpha-dependent maturational arrest. Biochim. Biophys. Acta 1862, 1013�. doi: 10.1016/j.bbalip.2017.06.014

Bernardo, A., Levi, G., and Minghetti, L. (2000). Role of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and its natural ligand 15-deoxy-Delta12, 14-prostaglandin J2 in the regulation of microglial functions. Eur. J. Neurosci. 12, 2215�. doi: 10.1046/j.1460-9568.2000.00110.x

Bernardo, A., and Minghetti, L. (2006). PPAR-gamma agonists as regulators of microglial activation and brain inflammation. Curr. Pharm. Des. 12, 93�. doi: 10.2174/138161206780574579

Berrabah, W., Aumercier, P., Lefebvre, P., and Staels, B. (2011). Control of nuclear receptor activities in metabolism by post-translational modifications. FEBS Lett. 585, 1640�. doi: 10.1016/j.febslet.2011.03.066

Bhatia, H. S., Agrawal, R., Sharma, S., Huo, Y.-X., Ying, Z., and Gomez-Pinilla, F. (2011). Omega-3 fatty acid deficiency during brain maturation reduces neuronal and behavioral plasticity in adulthood. PLoS One 6:e28451. doi: 10.1371/journal.pone.0028451

Bonet-Costa, V., Herranz-Perez, V., Blanco-Gandia, M., Mas-Bargues, C., Ingles, M., Garcia-Tarraga, P., et al. (2016). Clearing amyloid-beta through PPARgamma/ApoE activation by Genistein is a treatment of experimental Alzheimer’s disease. J. Alzheimers Dis. 51, 701�. doi: 10.3233/JAD-151020

Boneva, N. B., Kaplamadzhiev, D. B., Sahara, S., Kikuchi, H., Pyko, I. V., Kikuchi, M., et al. (2011). Expression of fatty acid-binding proteins in adult hippocampal neurogenic niche of postischemic monkeys. Hippocampus 21, 162�. doi: 10.1002/hipo.20732

Braissant, O., Foufelle, F., Scotto, C., Dauca, M., and Wahli, W. (1996). Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 137, 354�. doi: 10.1210/endo.137.1.8536636

Briscoe, C. P., Tadayyon, M., Andrews, J. L., Benson, W. G., Chambers, J. K., Eilert, M. M., et al. (2003). The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278, 11303�. doi: 10.1074/jbc.M211495200

Brown, A. J., Goldsworthy, S. M., Barnes, A. A., Eilert, M. M., Tcheang, L., Daniels, D., et al. (2003). The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 278, 11312�. doi: 10.1074/jbc.M211609200

Brown, A. J., Jupe, S., and Briscoe, C. P. (2005). A family of fatty acid binding receptors. DNA Cell Biol. 24, 54�. doi: 10.1089/dna.2005.24.54

Brown, M., Roulson, J.-A., Hart, C. A., Tawadros, T., and Clarke, N. W. (2014). Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer. Br. J. Cancer 110, 2099�. doi: 10.1038/bjc.2014.99

Brunmeir, R., and Xu, F. (2018). Functional regulation of PPARs through post-translational modifications. Int. J. Mol. Sci. 19:E1738. doi: 10.3390/ijms19061738

Burns, R. N., Singh, M., Senatorov, I. S., and Moniri, N. H. (2014). Mechanisms of homologous and heterologous phosphorylation of FFA receptor 4 (GPR120): GRK6 and PKC mediate phosphorylation of Thr(3)(4)(7), Ser(3)(5)(0), and Ser(3)(5)(7) in the C-terminal tail. Biochem. Pharmacol. 87, 650�. doi: 10.1016/j.bcp.2013.12.016

Calder, P. C. (2015). Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469�. doi: 10.1016/j.bbalip.2014.08.010

Cao, D., Kevala, K., Kim, J., Moon, H.-S., Jun, S. B., Lovinger, D., et al. (2009). Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function. J. Neurochem. 111, 510�. doi: 10.1111/j.1471-4159.2009.06335.x

Capelli, D., Cerchia, C., Montanari, R., Loiodice, F., Tortorella, P., Laghezza, A., et al. (2016). Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode. Sci. Rep. 6:34792. doi: 10.1038/srep34792

Cartoni, C., Yasumatsu, K., Ohkuri, T., Shigemura, N., Yoshida, R., Godinot, N., et al. (2010). Taste preference for fatty acids is mediated by GPR40 and GPR120. J. Neurosci. 30, 8376�. doi: 10.1523/JNEUROSCI.0496-10.2010

Chalon, S. (2006). Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot. Essent. Fatty Acids 75, 259�. doi: 10.1016/j.plefa.2006.07.005

Chalon, S., Delion-Vancassel, S., Belzung, C., Guilloteau, D., Leguisquet, A. M., Besnard, J. C., et al. (1998). Dietary fish oil affects monoaminergic neurotransmission and behavior in rats. J. Nutr. 128, 2512�. doi: 10.1093/jn/128.12.2512

Chan, R. B., Oliveira, T. G., Cortes, E. P., Honig, L. S., Duff, K. E., Small, S. A., et al. (2012). Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J. Biol. Chem. 287, 2678�. doi: 10.1074/jbc.M111.274142

Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T. P., et al. (2008). Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA. Nature 456, 350�. doi: 10.1038/nature07413

Chang, P. K.-Y., Khatchadourian, A., McKinney, R. A., and Maysinger, D. (2015). Docosahexaenoic acid (DHA): a modulator of microglia activity and dendritic spine morphology. J. Neuroinflammation 12:34. doi: 10.1186/s12974-015-0244-5

Chen, C. T., Green, J. T., Orr, S. K., and Bazinet, R. P. (2008). Regulation of brain polyunsaturated fatty acid uptake and turnover. Prostaglandins Leukot. Essent. Fatty Acids 79, 85�. doi: 10.1016/j.plefa.2008.09.003

Chen, J.-J., Gong, Y.-H., and He, L. (2019). Role of GPR40 in pathogenesis and treatment of Alzheimer’s disease and type 2 diabetic dementia. J. Drug Target. 27, 347�. doi: 10.1080/1061186X.2018.1491979

Chen, Q., Qiu, F., Zhou, K., Matlock, H. G., Takahashi, Y., Rajala, R. V. S., et al. (2017). Pathogenic role of microRNA-21 in diabetic retinopathy through downregulation of PPARalpha. Diabetes 66, 1671�. doi: 10.2337/db16-1246

Cheng, A., Shinoda, Y., Yamamoto, T., Miyachi, H., and Fukunaga, K. (2019). Development of FABP3 ligands that inhibit arachidonic acid-induced alpha-synuclein oligomerization. Brain Res. 1707, 190�. doi: 10.1016/j.brainres.2018.11.036

Cheon, M. S., Kim, S. H., Fountoulakis, M., and Lubec, G. (2003). “Heart type fatty acid binding protein (H-FABP) is decreased in brains of patients with Down syndrome and Alzheimer’s disease,” in Advances in Down Syndrome Research. Journal of Neural Transmission Supplement 67, ed. G. Lubec (Vienna: Springer), 225�. doi: 10.1007/978-3-7091-6721-2_20

Chistyakov, D. V., Aleshin, S. E., Astakhova, A. A., Sergeeva, M. G., and Reiser, G. (2015). Regulation of peroxisome proliferator-activated receptors (PPAR) α and -γ Of rat brain astrocytes in the course of activation by toll-like receptor agonists. J. Neurochem. 134, 113�. doi: 10.1111/jnc.13101

Chornenkyy, Y., Wang, W.-X., Wei, A., and Nelson, P. T. (2019). Alzheimer’s disease and type 2 diabetes mellitus are distinct diseases with potential overlapping metabolic dysfunction upstream of observed cognitive decline. Brain Pathol. 29, 3�. doi: 10.1111/bpa.12655

Civelli, O. (2005). GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends Pharmacol. Sci. 26, 15�. doi: 10.1016/j.tips.2004.11.005

Colina, C., Puhl, H. L. III, and Ikeda, S. R. (2018). Selective tracking of FFAR3-expressing neurons supports receptor coupling to N-type calcium channels in mouse sympathetic neurons. Sci. Rep. 8:17379. doi: 10.1038/s41598-018-35690-z

Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B., and Landreth, G. E. (2000). Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J. Neurosci. 20, 558�. doi: 10.1523/JNEUROSCI.20-02-00558.2000

Conklin, S. M., Runyan, C. A., Leonard, S., Reddy, R. D., Muldoon, M. F., and Yao, J. K. (2010). Age-related changes of n-3 and n-6 polyunsaturated fatty acids in the anterior cingulate cortex of individuals with major depressive disorder. Prostaglandins Leukot. Essent. Fatty Acids 82, 111�. doi: 10.1016/j.plefa.2009.12.002

Corona, J. C., and Duchen, M. R. (2015). PPAR c and PGC-1 a as Therapeutic Targets in Parkinson ’ s. Neurochem. Res. 40, 308�. doi: 10.1007/s11064-014-1377-0

Corona, J. C., and Duchen, M. R. (2016). PPARgamma as a therapeutic target to rescue mitochondrial function in neurological disease. Free Radic. Biol. Med. 100, 153�. doi: 10.1016/j.freeradbiomed.2016.06.023

Correll, C. C., and McKittrick, B. A. (2014). Biased ligand modulation of seven transmembrane receptors (7TMRs): functional implications for drug discovery. J. Med. Chem. 57, 6887�. doi: 10.1021/jm401677g

Corton, J. C., Anderson, S. P., and Stauber, A. (2000). Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu. Rev. Pharmacol. Toxicol. 40, 491�. doi: 10.1146/annurev.pharmtox.40.1.491

Cristiano, L., Bernardo, A., and Cerù, M. P. (2001). Peroxisome proliferator-activated receptors (PPARs) and peroxisomes in rat cortical and cerebellar astrocytes. J. Neurocytol. 30, 671�. doi: 10.1023/A:1016525716209

Cullingford, T. E., Bhakoo, K., Peuchen, S., Dolphin, C. T., Patel, R., and Clark, J. B. (1998). Distribution of mRNAs encoding the peroxisome proliferator-activated receptor alpha, beta, and gamma and the retinoid X receptor α, β, and γ in rat central nervous system. J. Neurochem. 70, 1366�. doi: 10.1046/j.1471-4159.1998.70041366.x

De Leon, M., Welcher, A. A., Nahin, R. H., Liu, Y., Ruda, M. A., Shooter, E. M., et al. (1996). Fatty acid binding protein is induced in neurons of the dorsal root ganglia after peripheral nerve injury. J. Neurosci. Res. 44, 283�. doi: 10.1002/(sici)1097-4547(19960501)44:3𼊃::aid-jnr9ϣ.0.co2-c

De Nuccio, C., Bernardo, A., Cruciani, C., De Simone, R., Visentin, S., and Minghetti, L. (2015). Peroxisome proliferator activated receptor-gamma agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: effects on mitochondrial functions and differentiation. Exp. Neurol. 271, 506�. doi: 10.1016/j.expneurol.2015.07.014

De Rosa, A., Pellegatta, S., Rossi, M., Tunici, P., Magnoni, L., Speranza, M. C., et al. (2012). A radial glia gene marker, fatty acid binding protein 7 (FABP7), is involved in proliferation and invasion of glioblastoma cells. PLoS One 7:e52113. doi: 10.1371/journal.pone.0052113PONE-D-12-11234

DeArmond, S. J., Deibler, G. E., Bacon, M., Kies, M. W., and Eng, L. F. (1980). A neurochemical and immunocytochemical study of P2 protein in human and bovine nervous systems. J. Histochem. Cytochem. 28, 1275�. doi: 10.1177/28.12.6785343

Delion, S., Chalon, S., Guilloteau, D., Besnard, J. C., and Durand, G. (1996). alpha-Linolenic acid dietary deficiency alters age-related changes of dopaminergic and serotoninergic neurotransmission in the rat frontal cortex. J. Neurochem. 66, 1582�. doi: 10.1046/j.1471-4159.1996.66041582.x

Dennis, E. A., and Norris, P. C. (2015). Eicosanoid storm in infection and inflammation. Nat. Rev. Immunol. 15, 511�. doi: 10.1038/nri3859

Dharap, A., Pokrzywa, C., Murali, S., Kaimal, B., and Vemuganti, R. (2015). Mutual induction of transcription factor PPARgamma and microRNAs miR-145 and miR-329. J. Neurochem. 135, 139�. doi: 10.1111/jnc.13220

Di Loreto, S., D𠆚ngelo, B., D𠆚mico, M. A., Benedetti, E., Cristiano, L., Cinque, B., et al. (2007). PPARbeta agonists trigger neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. J. Cell. Physiol. 211, 837�. doi: 10.1002/jcp.20996

Diaz, C., Angelloz-Nicoud, P., and Pihan, E. (2018). Modeling and Deorphanization of Orphan GPCRs. Methods Mol. Biol. 1705, 413�. doi: 10.1007/978-1-4939-7465-8_21

Dickey, A. S., Pineda, V. V., Tsunemi, T., Liu, P. P., Miranda, H. C., Gilmore-Hall, S. K., et al. (2016). PPAR-delta is repressed in Huntington’s disease, is required for normal neuronal function and can be targeted therapeutically. Nat. Med. 22, 37�. doi: 10.1038/nm.4003

Dietschy, J. M., and Turley, S. D. (2001). Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12, 105�.

Dietschy, J. M., and Turley, S. D. (2004). Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J. Lipid Res. 45, 1375�. doi: 10.1194/jlr.R400004-JLR200

Diezko, R., and Suske, G. (2013). Ligand binding reduces SUMOylation of the peroxisome proliferator-activated receptor gamma (PPARgamma) activation function 1 (AF1) domain. PLoS One 8:e66947. doi: 10.1371/journal.pone.0066947

Dorsam, R. T., and Gutkind, J. S. (2007). G-protein-coupled receptors and cancer. Nat. Rev. Cancer 7, 79�. doi: 10.1038/nrc2069

Dragano, N. R. V., Solon, C., Ramalho, A. F., de Moura, R. F., Razolli, D. S., Christiansen, E., et al. (2017). Polyunsaturated fatty acid receptors, GPR40 and GPR120, are expressed in the hypothalamus and control energy homeostasis and inflammation. J. Neuroinflammation 14:91. doi: 10.1186/s12974-017-0869-7

Dyall, S. C. (2017). Interplay between n-3 and n-6 long-chain polyunsaturated fatty acids and the endocannabinoid system in brain protection and repair. Lipids 52, 885�. doi: 10.1007/s11745-017-4292-8

Dyall, S. C., and Michael-Titus, A. T. (2008). Neurological benefits of omega-3 fatty acids. Neuromolecular Med. 10, 219�. doi: 10.1007/s12017-008-8036-z

Echeverria, F., Ortiz, M., Valenzuela, R., and Videla, L. A. (2016). Long-chain polyunsaturated fatty acids regulation of PPARs, signaling: Relationship to tissue development and aging. Prostaglandins Leukot. Essent. Fatty Acids 114, 28�. doi: 10.1016/j.plefa.2016.10.001

Edmond, J., Higa, T. A., Korsak, R. A., Bergner, E. A., and Lee, W. N. (1998). Fatty acid transport and utilization for the developing brain. J. Neurochem. 70, 1227�. doi: 10.1046/j.1471-4159.1998.70031227.x

Engelstoft, M. S., Park, W.-M., Sakata, I., Kristensen, L. V., Husted, A. S., Osborne-Lawrence, S., et al. (2013). Seven transmembrane G protein-coupled receptor repertoire of gastric ghrelin cells. Mol. Metab. 2, 376�. doi: 10.1016/j.molmet.2013.08.006

Etschmaier, K., Becker, T., Eichmann, T. O., Schweinzer, C., Scholler, M., Tam-Amersdorfer, C., et al. (2011). Adipose triglyceride lipase affects triacylglycerol metabolism at brain barriers. J. Neurochem. 119, 1016�. doi: 10.1111/j.1471-4159.2011.07498.x

Falomir-Lockhart, L. J., Franchini, G. R., Guerbi, M. X., Storch, J., and Córsico, B. (2011). Interaction of enterocyte FABPs with phospholipid membranes: clues for specific physiological roles. Biochim. Biophys. Acta 1811, 452�. doi: 10.1016/j.bbalip.2011.04.005

Falomir-Lockhart, L. J., Laborde, L., Kahn, P. C., Storch, J., Córsico, B., Falomir Lockhart, L. J., et al. (2006). Protein-membrane interaction and fatty acid transfer from intestinal fatty acid-binding protein to membranes. Support for a multistep process. J. Biol. Chem. 281, 13979�. doi: 10.1074/jbc.M511943200

Favrelere, S., Stadelmann-Ingrand, S., Huguet, F., De Javel, D., Piriou, A., Tallineau, C., et al. (2000). Age-related changes in ethanolamine glycerophospholipid fatty acid levels in rat frontal cortex and hippocampus. Neurobiol. Aging 21, 653�. doi: 10.1016/S0197-4580(00)00170-6

Fernandis, A. Z., and Wenk, M. R. (2007). Membrane lipids as signaling molecules. Curr. Opin. Lipidol. 18, 121�. doi: 10.1097/MOL.0b013e328082e4d5

Ferreira, L. S. S., Fernandes, C. S., Vieira, M. N. N., and De Felice, F. G. (2018). Insulin Resistance in Alzheimer’s Disease. Front. Neurosci. 12:830. doi: 10.3389/fnins.2018.00830

Foti, S. B., Chou, A., Moll, A. D., and Roskams, A. J. (2013). HDAC inhibitors dysregulate neural stem cell activity in the postnatal mouse brain. Int. J. Dev. Neurosci. 31, 434�. doi: 10.1016/j.ijdevneu.2013.03.008

Fredriksson, R., Höglund, P. J., Gloriam, D. E., Lagerström, M. C., and Schiöth, H. B. (2003). Seven evolutionarily conserved human rhodopsin G protein-coupled receptors lacking close relatives. FEBS Lett. 554, 381�. doi: 10.1016/S0014-5793(03)01196-7

Freitas, H. R., Isaac, A. R., Malcher-Lopes, R., Diaz, B. L., Trevenzoli, I. H., and De Melo Reis, R. A. (2017). Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr. Neurosci. 21, 695�. doi: 10.1080/1028415X.2017.1347373

Fu, Y., Zhen, J., and Lu, Z. (2017). Synergetic neuroprotective effect of docosahexaenoic acid and aspirin in SH-Y5Y by inhibiting miR-21 and activating RXRalpha and PPARalpha. DNA Cell Biol. 36, 482�. doi: 10.1089/dna.2017.3643

Gharami, K., Das, M., and Das, S. (2015). Essential role of docosahexaenoic acid towards development of a smarter brain. Neurochem. Int. 89, 51�. doi: 10.1016/j.neuint.2015.08.014

Glass, C. K., and Saijo, K. (2010). Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol. 10, 365�. doi: 10.1038/nri2748

Glomset, J. A. (2006). Role of docosahexaenoic acid in neuronal plasma membranes. Sci. STKE 2006:pe6. doi: 10.1126/stke.3212006pe6

Gray, S. L., Dalla Nora, E., and Vidal-Puig, A. J. (2005). Mouse models of PPAR-gamma deficiency: dissecting PPAR-gamma’s role in metabolic homoeostasis. Biochem. Soc. Trans. 33, 1053�. doi: 10.1042/BST20051053

Greenfield, S., Brostoff, S., Eylar, E. H., and Morell, P. (1973). Protein composition of myelin of the peripheral nervous system. J. Neurochem. 20, 1207�. doi: 10.1111/j.1471-4159.1973.tb00089.x

Guajardo, M. H., Terrasa, A. M., and Catala, A. (2002). Retinal fatty acid binding protein reduce lipid peroxidation stimulated by long-chain fatty acid hydroperoxides on rod outer segments. Biochim. Biophys. Acta 1581, 65�. doi: 10.1016/S1388-1981(02)00121-X

Gupta, S., Knight, A. G., Gupta, S., Keller, J. N., and Bruce-Keller, A. J. (2012). Saturated long-chain fatty acids activate inflammatory signaling in astrocytes. J. Neurochem. 120, 1060�. doi: 10.1111/j.1471-4159.2012.07660.x

Hall, M. G., Quignodon, L., and Desvergne, B. (2008). Peroxisome proliferator-activated receptor β/δ in the brain: Facts and hypothesis. PPAR Res. 2008:780452. doi: 10.1155/2008/780452

Hanhoff, T., L࿌ke, C., and Spener, F. (2002). Insights into binding of fatty acids by fatty acid binding proteins. Mol. Cell. Biochem. 239, 45�. doi: 10.1023/A:1020502624234

Hara, T., Kimura, I., Inoue, D., Ichimura, A., and Hirasawa, A. (2013). Free fatty acid receptors and their role in regulation of energy metabolism. Rev. Physiol. Biochem. Pharmacol. 164, 77�. doi: 10.1007/112_2013_13

Heldin, C., Lu, B., Evans, R., and Gutkind, J. S. (2016). Signals and receptors. Cold Spring Harb. Perspect. Biol. 8:a005900. doi: 10.1101/cshperspect.a005900

Heneka, M. T., and Landreth, G. E. (2007). PPARs in the brain. Biochim. Biophys. Acta 1771, 1031�. doi: 10.1016/j.bbalip.2007.04.016

Herr, F. M., Aronson, J., and Storch, J. (1996). Role of portal region lysine residues in electrostatic interactions between heart fatty acid binding protein and phospholipid membranes. Biochemistry 35, 1296�. doi: 10.1021/bi952204b

Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., et al. (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11, 90�. doi: 10.1038/nm1168

Hirsch, M. M., Deckmann, I., Fontes-Dutra, M., Bauer-Negrini, G., Della-Flora Nunes, G., Nunes, W., et al. (2018). Behavioral alterations in autism model induced by valproic acid and translational analysis of circulating microRNA. Food Chem. Toxicol. 115, 336�. doi: 10.1016/j.fct.2018.02.061

Ho, J. D., Chau, B., Rodgers, L., Lu, F., Wilbur, K. L., Otto, K. A., et al. (2018). Structural basis for GPR40 allosteric agonism and incretin stimulation. Nat. Commun. 9:1645. doi: 10.1038/s41467-017-01240-w

Holliday, N. D., Watson, S.-J., and Brown, A. J. H. (2012). Drug discovery opportunities and challenges at g protein coupled receptors for long chain free fatty acids. Front. Endocrinol. 2:112. doi: 10.3389/fendo.2011.00112

Hostetler, H. A., McIntosh, A. L., Atshaves, B. P., Storey, S. M., Payne, H. R., Kier, A. B., et al. (2009). L-FABP directly interacts with PPAR alpha in cultured primary hepatocytes. J. Lipid Res. 50, 1663�. doi: 10.1194/jlr.M900058-JLR200

Hudson, B. D., Shimpukade, B., Milligan, G., and Ulven, T. (2014). The molecular basis of ligand interaction at free fatty acid receptor 4 (FFA4/GPR120). J. Biol. Chem. 289, 20345�. doi: 10.1074/jbc.M114.561449

Hunsberger, J. G., Fessler, E. B., Chibane, F. L., Leng, Y., Maric, D., Elkahloun, A. G., et al. (2013). Mood stabilizer-regulated miRNAs in neuropsychiatric and neurodegenerative diseases: identifying associations and functions. Am. J. Transl. Res. 5, 450�.

Hussain, G., Schmitt, F., Loeffler, J.-P., and de Aguilar, J.-L. G. (2013). Fatting the brain: a brief of recent research. Front. Cell. Neurosci. 7:144. doi: 10.3389/fncel.2013.00144

Im, D.-S. (2004). Discovery of new G protein-coupled receptors for lipid mediators. J. Lipid Res. 45, 410�. doi: 10.1194/jlr.R300006-JLR200

Ingolfsson, H. I., Carpenter, T. S., Bhatia, H., Bremer, P.-T., Marrink, S. J., and Lightstone, F. C. (2017). Computational lipidomics of the neuronal plasma membrane. Biophys. J. 113, 2271�. doi: 10.1016/j.bpj.2017.10.017

Innes, J. K., and Calder, P. C. (2018). Omega-6 fatty acids and inflammation. Prostaglandins Leukot. Essent. Fatty Acids 132, 41�. doi: 10.1016/j.plefa.2018.03.004

Issemann, I., and Green, S. (1990). Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645�. doi: 10.1038/347645a0

Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., et al. (2003). Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422, 173�. doi: 10.1038/nature01478

Jana, M., Mondal, S., Gonzalez, F. J., and Pahan, K. (2012). Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor-beta. J. Biol. Chem. 287, 34134�. doi: 10.1074/jbc.M112.398552

Janesick, A., Wu, S. C., and Blumberg, B. (2015). Retinoic acid signaling and neuronal differentiation. Cell. Mol. Life Sci. 72, 1559�. doi: 10.1007/s00018-014-1815-9

Johnson, E. J., and Schaefer, E. J. (2006). Potential role of dietary n-3 fatty acids in the prevention of dementia and macular degeneration. Am. J. Clin. Nutr. 83, 1494S�S. doi: 10.1093/ajcn/83.6.1494S

Kaczocha, M., Rebecchi, M. J., Ralph, B. P., Teng, Y.-H. G., Berger, W. T., Galbavy, W., et al. (2014). Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia. PLoS One 9:e94200. doi: 10.1371/journal.pone.0094200

Kainu, T., Wikstrom, A. C., Gustafsson, J. A., and Pelto-Huikko, M. (1994). Localization of the peroxisome proliferator-activated receptor in the brain. Neuroreport 5, 2481�.

Kamata, Y., Shiraga, H., Tai, A., Kawamoto, Y., and Gohda, E. (2007). Induction of neurite outgrowth in PC12 cells by the medium-chain fatty acid octanoic acid. Neuroscience 146, 1073�. doi: 10.1016/j.neuroscience.2007.03.001

Katakura, M., Hashimoto, M., Shahdat, H. M., Gamoh, S., Okui, T., Matsuzaki, K., et al. (2009). Docosahexaenoic acid promotes neuronal differentiation by regulating basic helix-loop-helix transcription factors and cell cycle in neural stem cells. Neuroscience 160, 651�. doi: 10.1016/j.neuroscience.2009.02.057

Kenakin, T., and Christopoulos, A. (2013). Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12, 205�. doi: 10.1038/nrd3954

Khan, M. Z., Zhuang, X., and He, L. (2016). GPR40 receptor activation leads to CREB phosphorylation and improves cognitive performance in an Alzheimer’s disease mouse model. Neurobiol. Learn. Mem. 131, 46�. doi: 10.1016/j.nlm.2016.03.006

Kim, J. Y., Lee, H. J., Lee, S.-J., Jung, Y. H., Yoo, D. Y., Hwang, I. K., et al. (2017). Palmitic acid-BSA enhances amyloid-beta production through GPR40-mediated dual pathways in neuronal cells: Involvement of the Akt/mTOR/HIF-1alpha and Akt/NF-kappaB pathways. Sci. Rep. 7:4335. doi: 10.1038/s41598-017-04175-w

Kimura, I., Inoue, D., Maeda, T., Hara, T., Ichimura, A., Miyauchi, S., et al. (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U.S.A. 108, 8030�. doi: 10.1073/pnas.1016088108

Kitajka, K., Sinclair, A. J., Weisinger, R. S., Weisinger, H. S., Mathai, M., Jayasooriya, A. P., et al. (2004). Effects of dietary omega-3 polyunsaturated fatty acids on brain gene expression. Proc. Natl. Acad. Sci. U.S.A. 101, 10931�. doi: 10.1073/pnas.0402342101

Kostenis, E. (2004). A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol. Ther. 102, 243�. doi: 10.1016/j.pharmthera.2004.04.005

Kurtz, A., Zimmer, A., Schnutgen, F., Bruning, G., Spener, F., and Muller, T. (1994). The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development. Development 120, 2637�.

Labrousse, V. F., Nadjar, A., Joffre, C., Costes, L., Aubert, A., Gregoire, S., et al. (2012). Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice. PLoS One 7:e36861. doi: 10.1371/journal.pone.0036861

Lafourcade, M., Larrieu, T., Mato, S., Duffaud, A., Sepers, M., Matias, I., et al. (2011). Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat. Neurosci. 14, 345�. doi: 10.1038/nn.2736

Lampen, A., Carlberg, C., and Nau, H. (2001). Peroxisome proliferator-activated receptor delta is a specific sensor for teratogenic valproic acid derivatives. Eur. J. Pharmacol. 431, 25�. doi: 10.1016/s0014-2999(01)01423-6

Landrier, J.-F., Thomas, C., Grober, J., Duez, H., Percevault, F., Souidi, M., et al. (2004). Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent. J. Biol. Chem. 279, 45512�. doi: 10.1074/jbc.M407461200

Laschet, C., Dupuis, N., and Hanson, J. (2018). The G protein-coupled receptors deorphanization landscape. Biochem. Pharmacol. 153, 62�. doi: 10.1016/j.bcp.2018.02.016

Lein, E. S., Hawrylycz, M. J., Ao, N., Ayres, M., Bensinger, A., Bernard, A., et al. (2007). Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168�. doi: 10.1038/nature05453

Leong, C., Zhai, D., Kim, B., Yun, S.-W., and Chang, Y.-T. (2013). Neural stem cell isolation from the whole mouse brain using the novel FABP7-binding fluorescent dye, CDr3. Stem Cell Res. 11, 1314�. doi: 10.1016/j.scr.2013.09.002

Leoni, V., and Caccia, C. (2011). Oxysterols as biomarkers in neurodegenerative diseases. Chem. Phys. Lipids 164, 515�. doi: 10.1016/j.chemphyslip.2011.04.002

Li, Z., Chen, Y., Zhang, Y., Jiang, H., Liu, Y., Chen, Y., et al. (2018a). Structure-based design of free fatty acid receptor 1 agonists bearing non-biphenyl scaffold. Bioorg. Chem. 80, 296�. doi: 10.1016/j.bioorg.2018.06.039

Li, Z., Chen, Y., Zhou, Z., Deng, L., Xu, Y., Hu, L., et al. (2019). Discovery of first-in-class thiazole-based dual FFA1/PPARdelta agonists as potential anti-diabetic agents. Eur. J. Med. Chem. 164, 352�. doi: 10.1016/j.ejmech.2018.12.069

Li, Z., Qiu, Q., Geng, X., Yang, J., Huang, W., and Qian, H. (2016). Free fatty acid receptor agonists for the treatment of type 2 diabetes: drugs in preclinical to phase II clinical development. Expert Opin. Investig. Drugs 25, 871�. doi: 10.1080/13543784.2016.1189530

Li, Z., Xu, X., Hou, J., Wang, S., Jiang, H., and Zhang, L. (2018b). Structure-based optimization of free fatty acid receptor 1 agonists bearing thiazole scaffold. Bioorg. Chem. 77, 429�. doi: 10.1016/j.bioorg.2018.01.039

Li, Z., Zhou, Z., Deng, F., Li, Y., Zhang, D., and Zhang, L. (2018c). Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARgamma and PPARdelta. Eur. J. Med. Chem. 159, 267�. doi: 10.1016/j.ejmech.2018.09.071

Liou, H. L., Kahn, P. C., and Storch, J. (2002). Role of the helical domain in fatty acid transfer from adipocyte and heart fatty acid-binding proteins to membranes - Analysis of chimeric proteins. J. Biol. Chem. 277, 1806�. doi: 10.1074/jbc.M107987200

Liu, R.-Z., Li, X., and Godbout, R. (2008). A novel fatty acid-binding protein (FABP) gene resulting from tandem gene duplication in mammals: transcription in rat retina and testis. Genomics 92, 436�. doi: 10.1016/j.ygeno.2008.08.003

Liu, R. Z., Mita, R., Beaulieu, M., Gao, Z., and Godbout, R. (2010). Fatty acid binding proteins in brain development and disease. Int. J. Dev. Biol. 54, 1229�. doi: 10.1387/ijdb.092976rl092976rl

Liu, X. S., Chopp, M., Kassis, H., Jia, L. F., Hozeska-Solgot, A., Zhang, R. L., et al. (2012). Valproic acid increases white matter repair and neurogenesis after stroke. Neuroscience 220, 313�. doi: 10.1016/j.neuroscience.2012.06.012

Liu, Y., Longo, L. D., and De Leon, M. (2000). In situ and immunocytochemical localization of E-FABP mRNA and protein during neuronal migration and differentiation in the rat brain. Brain Res. 852, 16�. doi: 10.1016/s0006-8993(99)02158-7

Lu, J., Byrne, N., Wang, J., Bricogne, G., Brown, F. K., Chobanian, H. R., et al. (2017). Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40. Nat. Struct. Mol. Biol. 24, 570�. doi: 10.1038/nsmb.3417

Lundell, K., Thulin, P., Hamsten, A., and Ehrenborg, E. (2007). Alternative splicing of human peroxisome proliferator-activated receptor delta (PPAR delta): effects on translation efficiency and trans-activation ability. BMC Mol. Biol. 8:70. doi: 10.1186/1471-2199-8-70

Ma, D., Lu, L., Boneva, N. B., Warashina, S., Kaplamadzhiev, D. B., Mori, Y., et al. (2008). Expression of free fatty acid receptor GPR40 in the neurogenic niche of adult monkey hippocampus. Hippocampus 18, 326�. doi: 10.1002/hipo.20393

Ma, D., Tao, B., Warashina, S., Kotani, S., Lu, L., Kaplamadzhiev, D. B., et al. (2007). Expression of free fatty acid receptor GPR40 in the central nervous system of adult monkeys. Neurosci. Res. 58, 394�. doi: 10.1016/j.neures.2007.05.001

Ma, D., Zhang, M., Larsen, C. P., Xu, F., Hua, W., Yamashima, T., et al. (2010). DHA promotes the neuronal differentiation of rat neural stem cells transfected with GPR40 gene. Brain Res. 1330, 1𠄸. doi: 10.1016/j.brainres.2010.03.002

Magnan, C., Levin, B. E., and Luquet, S. (2015). Brain lipid sensing and the neural control of energy balance. Mol. Cell. Endocrinol. 418(Pt. 1), 3𠄸. doi: 10.1016/j.mce.2015.09.019

Mancini, A. D., Bertrand, G., Vivot, K., Carpentier, E., Tremblay, C., Ghislain, J., et al. (2015). beta-Arrestin recruitment and biased agonism at free fatty acid receptor 1. J. Biol. Chem. 290, 21131�. doi: 10.1074/jbc.M115.644450

Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83, 835�. doi: 10.1016/0092-8674(95)90199-X

Martin, G. G., McIntosh, A. L., Huang, H., Gupta, S., Atshaves, B. P., Landrock, K. K., et al. (2013). The human liver fatty acid binding protein T94A variant alters the structure, stability, and interaction with fibrates. Biochemistry 52, 9347�. doi: 10.1021/bi401014k

McNamara, R. K., and Carlson, S. E. (2006). Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot. Essent. Fatty Acids 75, 329�. doi: 10.1016/j.plefa.2006.07.010

Miglio, G., Rattazzi, L., Rosa, A. C., and Fantozzi, R. (2009). PPARgamma stimulation promotes neurite outgrowth in SH-SY5Y human neuroblastoma cells. Neurosci. Lett. 454, 134�. doi: 10.1016/j.neulet.2009.03.014

Mobraten, K., Haug, T. M., Kleiveland, C. R., and Lea, T. (2013). Omega-3 and omega-6 PUFAs induce the same GPR120-mediated signalling events, but with different kinetics and intensity in Caco-2 cells. Lipids Health Dis. 12:101. doi: 10.1186/1476-511X-12-101

Moreno, S., Farioli-vecchioli, S., and Cerù, M. P. (2004). Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 123, 131�. doi: 10.1016/j.neuroscience.2003.08.064

Motley, W. W., Palaima, P., Yum, S. W., Gonzalez, M. A., Tao, F., Wanschitz, J. V., et al. (2016). De novo PMP2 mutations in families with type 1 Charcot-Marie-Tooth disease. Brain 139, 1649�. doi: 10.1093/brain/aww055

Mounsey, R. B., Martin, H. L., Nelson, M. C., Evans, R. M., and Teismann, P. (2015). The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson’s disease. Neuroscience 300, 576�. doi: 10.1016/j.neuroscience.2015.05.048

Muller, M. M., Lehmann, R., Klassert, T. E., Reifenstein, S., Conrad, T., Moore, C., et al. (2017). Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFalpha expression. Sci. Rep. 7:838. doi: 10.1038/s41598-017-00828-y

Murillo-Rodriguez, E. (2017). The role of nuclear receptor pparalpha in the sleep-wake cycle modulation. A tentative approach for treatment of sleep disorders. Curr. Drug Deliv. 14, 473�. doi: 10.2174/1567201814666161109123803

Murphy, E. J., Owada, Y., Kitanaka, N., Kondo, H., and Glatz, J. F. C. (2005). Brain arachidonic acid incorporation is decreased in heart fatty acid binding protein gene-ablated mice. Biochemistry 44, 6350�. doi: 10.1021/bi047292r

Nakamoto, K., Nishinaka, T., Matsumoto, K., Kasuya, F., Mankura, M., Koyama, Y., et al. (2012). Involvement of the long-chain fatty acid receptor GPR40 as a novel pain regulatory system. Brain Res. 1432, 74�. doi: 10.1016/j.brainres.2011.11.012

Niculescu, M. D., Lupu, D. S., and Craciunescu, C. N. (2011). Maternal alpha-linolenic acid availability during gestation and lactation alters the postnatal hippocampal development in the mouse offspring. Int. J. Dev. Neurosci. 29, 795�. doi: 10.1016/j.ijdevneu.2011.09.006

Nikaido, Y., Koyama, Y., Yoshikawa, Y., Furuya, T., and Takeda, S. (2015). Mutation analysis and molecular modeling for the investigation of ligand-binding modes of GPR84. J. Biochem. 157, 311�. doi: 10.1093/jb/mvu075

Nohr, M. K., Pedersen, M. H., Gille, A., Egerod, K. L., Engelstoft, M. S., Husted, A. S., et al. (2013). GPR41/FFAR3 and GPR43/FFAR2 as cosensors for short-chain fatty acids in enteroendocrine cells vs FFAR3 in enteric neurons and FFAR2 in enteric leukocytes. Endocrinology 154, 3552�. doi: 10.1210/en.2013-1142

Noy, N. (2016). Non-classical transcriptional activity of retinoic acid. Subcell. Biochem. 81, 179�. doi: 10.1007/978-94-024-0945-1_7

Offermanns, S. (2013). Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu. Rev. Pharmacol. Toxicol. 54, 407�. doi: 10.1146/annurev-pharmtox-011613-135945

Oikawa, H., and Sng, J. C. G. (2016). Valproic acid as a microRNA modulator to promote neurite outgrowth. Neural Regen. Res. 11, 1564�. doi: 10.4103/1673-5374.193227

Orr, S. K., Trepanier, M. O., and Bazinet, R. P. (2013). n-3 Polyunsaturated fatty acids in animal models with neuroinflammation. Prostaglandins Leukot. Essent. Fatty Acids 88, 97�. doi: 10.1016/j.plefa.2012.05.008

Orth, M., and Bellosta, S. (2012). Cholesterol: its regulation and role in central nervous system disorders. Cholesterol 2012:292598. doi: 10.1155/2012/292598

Ory, J., Kane, C. D., Simpson, M. A., Banaszak, L. J., and Bernlohr, D. A. (1997). Biochemical and crystallographic analyses of a portal mutant of the adipocyte lipid-binding protein. J. Biol. Chem. 272, 9793�. doi: 10.1074/jbc.272.15.9793

O’Sullivan, S. E. (2007). Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors. Br. J. Pharmacol. 152, 576�. doi: 10.1038/sj.bjp.0707423

Owada, Y. (2008). Fatty acid binding protein: localization and functional significance in the brain. Tohoku J. Exp. Med. 214, 213�. doi: 10.1620/tjem.214.213

Owada, Y., Yoshimoto, T., and Kondo, H. (1996). Spatio-temporally differential expression of genes for three members of fatty acid binding proteins in developing and mature rat brains. J. Chem. Neuroanat. 12, 113�. doi: 10.1016/s0891-0618(96)00192-5

Pelsers, M. M., Hanhoff, T., Van Der Voort, D., Arts, B., Peters, M., Ponds, R., et al. (2004). Brain- and heart-type fatty acid-binding proteins in the brain: Tissue distribution and clinical utility. Clin. Chem. 50, 1568�. doi: 10.1373/clinchem.2003.030361

Pelsers, M. M., Hermens, W. T., and Glatz, J. F. C. (2005). Fatty acid-binding proteins as plasma markers of tissue injury. Clin. Chim. Acta 352, 15�. doi: 10.1016/j.cccn.2004.09.001

Pepino, M. Y., Kuda, O., Samovski, D., and Abumrad, N. A. (2014). Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu. Rev. Nutr. 34, 281�. doi: 10.1146/annurev-nutr-071812-161220

Peters, B. D., Duran, M., Vlieger, E. J., Majoie, C. B., den Heeten, G. J., Linszen, D. H., et al. (2009). Polyunsaturated fatty acids and brain white matter anisotropy in recent-onset schizophrenia: a preliminary study. Prostaglandins Leukot. Essent. Fatty Acids 81, 61�. doi: 10.1016/j.plefa.2009.04.007

Prolla, T. A., and Mattson, M. P. (2001). Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction. Trends Neurosci. 24, S21–S31. doi: 10.1016/S0166-2236(01)00005-4

Punetha, J., Mackay-Loder, L., Harel, T., Coban-Akdemir, Z., Jhangiani, S. N., Gibbs, R. A., et al. (2018). Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: clinical gene panels versus genome-wide approaches to molecular diagnosis. Mol. Genet. Metab. 125, 302�. doi: 10.1016/j.ymgme.2018.08.005

Rademacher, M., Zimmerman, A. W., Ruterjans, H., Veerkamp, J. H., and Lucke, C. (2002). Solution structure of fatty acid-binding protein from human brain. Mol. Cell. Biochem. 239, 61�. doi: 10.1023/A:1020566909213

Rautureau, Y., Paradis, P., and Schiffrin, E. L. (2017). Generation of a mouse model with smooth muscle cell specific loss of the expression of PPARgamma. Methods Mol. Biol. 1527, 381�. doi: 10.1007/978-1-4939-6625-7_30

Reddy, D. S. (2010). Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog. Brain Res. 186, 113�. doi: 10.1016/B978-0-444-53630-3.00008-7

Reese, A. J., and Banaszak, L. J. (2004). Specificity determinants for lipids bound to beta-barrel proteins. J. Lipid Res. 45, 232�. doi: 10.1194/jlr.M300113-JLR200

Richieri, G. V., Ogata, R. T., Zimmerman, A. W., Veerkamp, J. H., and Kleinfeld, A. M. (2000). Fatty acid binding proteins from different tissues show distinct patterns of fatty acid interactions. Biochemistry 39, 7197�. doi: 10.1021/bi000314z

Ricote, M., and Glass, C. K. (2007). PPARs and molecular mechanisms of transrepression. Biochim. Biophys. Acta 1771, 926�. doi: 10.1016/j.bbalip.2007.02.013

Rivera, P., Arrabal, S., Vargas, A., Blanco, E., Serrano, A., Pavon, F. J., et al. (2014). Localization of peroxisome proliferator-activated receptor alpha (PPARα) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) in cells expressing the Ca 2+ -binding proteins calbindin, calretinin, and parvalbumin in the adult rat hippocampus. Front. Neuroanat. 8:12. doi: 10.3389/fnana.2014.00012

Rocha, D. M., Caldas, A. P., Oliveira, L. L., Bressan, J., and Hermsdorff, H. H. (2016). Saturated fatty acids trigger TLR4-mediated inflammatory response. Atherosclerosis 244, 211�. doi: 10.1016/j.atherosclerosis.2015.11.015

Rohwedder, A., Zhang, Q., Rudge, S. A., and Wakelam, M. J. O. (2014). Lipid droplet formation in response to oleic acid in Huh-7 cells is mediated by the fatty acid receptor FFAR4. J. Cell Sci. 127, 3104�. doi: 10.1242/jcs.145854

Rombaldi Bernardi, J., de Souza Escobar, R., Ferreira, C. F., and Pelufo Silveira, P. (2012). Fetal and neonatal levels of omega-3: effects on neurodevelopment, nutrition, and growth. ScientificWorldJournal 2012:202473. doi: 10.1100/2012/202473

Roth, A. D., Leisewitz, A. V., Jung, J. E., Cassina, P., Barbeito, L., Inestrosa, N. C., et al. (2003). PPAR γ activators induce growth arrest and process extension in B12 oligodendrocyte-like cells and terminal differentiation of cultured oligodendrocytes. J. Neurosci. Res. 72, 425�. doi: 10.1002/jnr.10596

Roy, A., and Pahan, K. (2015). PPARalpha signaling in the hippocampus: crosstalk between fat and memory. J. Neuroimmune Pharmacol. 10, 30�. doi: 10.1007/s11481-014-9582-9

Sacchettini, J. C., Meininger, T. A., Lowe, J. B., Gordon, J. I., and Banaszak, L. J. (1987). Crystallization of rat intestinal fatty-acid binding protein - preliminary-x-ray data obtained from protein expressed in Escherichia-coli. J. Biol. Chem. 262, 5428�.

Saino-Saito, S., Nourani, R. M., Iwasa, H., Kondo, H., and Owada, Y. (2009). Discrete localization of various fatty-acid-binding proteins in various cell populations of mouse retina. Cell Tissue Res. 338, 191�. doi: 10.1007/s00441-009-0862-2

Saino-Saito, S., Suzuki, R., Tokuda, N., Abe, H., Kondo, H., and Owada, Y. (2010). Localization of fatty acid binding proteins (FABPs) in the cochlea of mice. Ann. Anat. 192, 210�. doi: 10.1016/j.aanat.2010.06.007

Samuel, B. S., Shaito, A., Motoike, T., Rey, F. E., Backhed, F., Manchester, J. K., et al. (2008). Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl. Acad. Sci. U.S.A. 105, 16767�. doi: 10.1073/pnas.0808567105

Sanchez-Font, M. F., Bosch-Comas, A., Gonzalez-Duarte, R., and Marfany, G. (2003). Overexpression of FABP7 in Down syndrome fetal brains is associated with PKNOX1 gene-dosage imbalance. Nucleic Acids Res. 31, 2769�. doi: 10.1093/nar/gkg396

Sanchez-Reyes, O. B., Romero-Avila, M. T., Castillo-Badillo, J. A., Takei, Y., Hirasawa, A., Tsujimoto, G., et al. (2014). Free fatty acids and protein kinase C activation induce GPR120 (free fatty acid receptor 4) phosphorylation. Eur. J. Pharmacol. 723, 368�. doi: 10.1016/j.ejphar.2013.11.003

Santos, M. J., Quintanilla, R. A., Toro, A., Grandy, R., Dinamarca, M. C., Godoy, J. A., et al. (2005). Peroxisomal proliferation protects from beta-amyloid neurodegeneration. J. Biol. Chem. 280, 41057�. doi: 10.1074/jbc.M505160200

Sarruf, D. A., Yu, F., Nguyen, H. T., Williams, D. L., Printz, R. L., Niswender, K. D., et al. (2009). Expression of peroxisome proliferator-activated receptor-γ in key neuronal subsets regulating glucose metabolism and energy homeostasis. Endocrinology 150, 707�. doi: 10.1210/en.2008-0899

Sasselli, V., Pachnis, V., and Burns, A. J. (2012). The enteric nervous system. Dev. Biol. 366, 64�. doi: 10.1016/j.ydbio.2012.01.012

Sastre, M., Klockgether, T., and Heneka, M. T. (2006). Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167�. doi: 10.1016/j.ijdevneu.2005.11.014

Sawzdargo, M., George, S. R., Nguyen, T., Xu, S., Kolakowski, L. F., and O𠆝owd, B. F. (1997). A cluster of four novel human g protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem. Biophys. Res. Commun. 239, 543�. doi: 10.1006/bbrc.1997.7513

Scandroglio, F., Venkata, J. K., Loberto, N., Prioni, S., Schuchman, E. H., Chigorno, V., et al. (2008). Lipid content of brain, brain membrane lipid domains, and neurons from acid sphingomyelinase deficient mice. J. Neurochem. 107, 329�. doi: 10.1111/j.1471-4159.2008.05591.x

Schug, T. T., Berry, D. C., Shaw, N. S., Travis, S. N., and Noy, N. (2007). Opposing effects of retinoic acid on cell growth result from alternate activation of two different nuclear receptors. Cell 129, 723�. doi: 10.1016/j.cell.2007.02.050

Schug, T. T., Berry, D. C., Toshkov, I. A., Cheng, L., Nikitin, A. Y., and Noy, N. (2008). Overcoming retinoic acid-resistance of mammary carcinomas by diverting retinoic acid from PPARbeta/delta to RAR. Proc. Natl. Acad. Sci. U.S.A. 105, 7546�. doi: 10.1073/pnas.0709981105

Senga, S., Kawaguchi, K., Kobayashi, N., Ando, A., and Fujii, H. (2018). A novel fatty acid-binding protein 5-estrogen-related receptor alpha signaling pathway promotes cell growth and energy metabolism in prostate cancer cells. Oncotarget 9, 31753�. doi: 10.18632/oncotarget.25878

Serhan, C. N. (2014). Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92�. doi: 10.1038/nature13479

Shang, J., Brust, R., Mosure, S. A., Bass, J., Munoz-Tello, P., Lin, H., et al. (2018). Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARgamma. eLife 7:e43320. doi: 10.7554/eLife.43320

Shao, D., Rangwala, S. M., Bailey, S. T., Krakow, S. L., Reginato, M. J., and Lazar, M. A. (1998). Interdomain communication regulating ligand binding by PPAR-gamma. Nature 396, 377�. doi: 10.1038/24634

Shioda, N., Yabuki, Y., Kobayashi, Y., Onozato, M., Owada, Y., and Fukunaga, K. (2014). FABP3 protein promotes alpha-synuclein oligomerization associated with 1-methyl-1,2,3,6-tetrahydropiridine-induced neurotoxicity. J. Biol. Chem. 289, 18957�. doi: 10.1074/jbc.M113.527341

Shioda, N., Yamamoto, Y., Watanabe, M., Binas, B., Owada, Y., and Fukunaga, K. (2010). Heart-type fatty acid binding protein regulates dopamine D2 receptor function in mouse brain. J. Neurosci. 30, 3146�. doi: 10.1523/JNEUROSCI.4140-09.2010

Smathers, R. L., and Petersen, D. R. (2011). The human fatty acid-binding protein family: evolutionary divergences and functions. Hum. Genomics 5, 170�.

Smith, A. J., Sanders, M. A., Juhlmann, B. E., Hertzel, A. V., and Bernlohr, D. A. (2008). Mapping of the hormone-sensitive lipase binding site on the adipocyte fatty acid-binding protein (AFABP). Identification of the charge quartet on the AFABP/aP2 helix-turn-helix domain. J. Biol. Chem. 283, 33536�. doi: 10.1074/jbc.M806732200

Sona, C., Kumar, A., Dogra, S., Kumar, B. A., Umrao, D., and Yadav, P. N. (2018). Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice. Neurobiol. Dis. 118, 94�. doi: 10.1016/j.nbd.2018.07.002

Song, T., Yang, Y., Zhou, Y., Wei, H., and Peng, J. (2017). GPR120: a critical role in adipogenesis, inflammation, and energy metabolism in adipose tissue. Cell. Mol. Life Sci. 74, 2723�. doi: 10.1007/s00018-017-2492-2

Srivastava, A., Yano, J., Hirozane, Y., Kefala, G., Gruswitz, F., Snell, G., et al. (2014). High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature 513, 124�. doi: 10.1038/nature13494

Stoddart, L. A., Smith, N. J., Jenkins, L., Brown, A. J., and Milligan, G. (2008). Conserved polar residues in transmembrane domains V, VI, and VII of free fatty acid receptor 2 and free fatty acid receptor 3 are required for the binding and function of short chain fatty acids. J. Biol. Chem. 283, 32913�. doi: 10.1074/jbc.M805601200

Storch, J., and Corsico, B. (2008). The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu. Rev. Nutr. 28, 73�. doi: 10.1146/annurev.nutr.27.061406.093710

Storch, J., and Thumser, A. E. (2010). Tissue-specific functions in the fatty acid-binding protein family. J. Biol. Chem. 285, 32679�. doi: 10.1074/jbc.R110.135210

Storch, J., and Thumser, A. E. A. (2000). The fatty acid transport function of fatty acid-binding proteins. Biochim. Biophys. Acta 1486, 28�. doi: 10.1016/S1388-1981(00)00046-9

Storch, J., Veerkamp, J. H., and Hsu, K. T. (2002). Similar mechanisms of fatty acid transfer from human anal rodent fatty acid-binding proteins to membranes: liver, intestine, heart muscle, and adipose tissue FABPs. Mol. Cell. Biochem. 239, 25�. doi: 10.1023/A:1020546321508

Sum, C. S., Tikhonova, I. G., Neumann, S., Engel, S., Raaka, B. M., Costanzi, S., et al. (2007). Identification of residues important for agonist recognition and activation in GPR40. J. Biol. Chem. 282, 29248�. doi: 10.1074/jbc.M705077200

Sunshine, H., and Iruela-Arispe, M. L. (2017). Membrane lipids and cell signaling. Curr. Opin. Lipidol. 28, 408�. doi: 10.1097/MOL.0000000000000443

Suzuki, M., Takaishi, S., Nagasaki, M., Onozawa, Y., Iino, I., Maeda, H., et al. (2013). Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J. Biol. Chem. 288, 10684�. doi: 10.1074/jbc.M112.420042

Taha, A. Y., Filo, E., Ma, D. W. L., and McIntyre Burnham, W. (2009). Dose-dependent anticonvulsant effects of linoleic and alpha-linolenic polyunsaturated fatty acids on pentylenetetrazol induced seizures in rats. Epilepsia 50, 72�. doi: 10.1111/j.1528-1167.2008.01731.x

The GTEx Consortium (2013). The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580�. doi: 10.1038/ng.2653

Thompson, J., Reese-Wagoner, A., and Banaszak, L. (1999). Liver fatty acid binding protein: species variation and the accommodation of different ligands. Biochim. Biophys. Acta 1441, 117�. doi: 10.1016/S1388-1981(99)00146-8

Tikhonova, I. G., Sum, C. S., Neumann, S., Thomas, C. J., Raaka, B. M., Costanzi, S., et al. (2007). Bidirectional, iterative approach to the structural delineation of the functional 𠇌hemoprint” in GPR40 for agonist recognition. J. Med. Chem. 50, 2981�. doi: 10.1021/jm0614782

Tzeng, J., Byun, J., Park, J. Y., Yamamoto, T., Schesing, K., Tian, B., et al. (2015). An Ideal PPAR response element bound to and activated by PPARalpha. PLoS One 10:e0134996. doi: 10.1371/journal.pone.0134996

Uauy, R., and Dangour, A. D. (2006). Nutrition in brain development and aging: role of essential fatty acids. Nutr. Rev. 64, S24–S33. doi: 10.1111/j.1753-4887.2006.tb00242.x

Uhlen, M., Fagerberg, L., Hallstrom, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., et al. (2015). Proteomics. Tissue-based map of the human proteome. Science 347:1260419. doi: 10.1126/science.1260419

Ulven, T. (2012). Short-chain free fatty acid receptors FFA2/GPR43 and FFA3/GPR41 as new potential therapeutic targets. Front. Endocrinol. 3:111. doi: 10.3389/fendo.2012.00111

van Gelder, B. M., Tijhuis, M., Kalmijn, S., and Kromhout, D. (2007). Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am. J. Clin. Nutr. 85, 1142�. doi: 10.1093/ajcn/85.4.1142

Vance, J. E. (2012). Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis. Model. Mech. 5, 746�. doi: 10.1242/dmm.010124

Veerkamp, J. H., and Zimmerman, A. W. (2001). Fatty acid-binding proteins of nervous tissue. J. Mol. Neurosci. 16, 133�.

Villapol, S. (2018). Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cell. Mol. Neurobiol. 38, 121�. doi: 10.1007/s10571-017-0554-5

Villegas-Comonfort, S., Takei, Y., Tsujimoto, G., Hirasawa, A., and Garc໚-Sáinz, J. A. (2017). Effects of arachidonic acid on FFA4 receptor: signaling, phosphorylation and internalization. Prostaglandins Leukot. Essent. Fat. Acids 117, 1�. doi: 10.1016/j.plefa.2017.01.013

von Bernhardi, R., Eugenin-von Bernhardi, J., Flores, B., and Eugenin Leon, J. (2016). Glial cells and integrity of the nervous system. Adv. Exp. Med. Biol. 949, 1�. doi: 10.1007/978-3-319-40764-7_1

Walder, B., Robin, X., Rebetez, M. M. L., Copin, J.-C., Gasche, Y., Sanchez, J.-C., et al. (2013). The prognostic significance of the serum biomarker heart-fatty acidic binding protein in comparison with s100b in severe traumatic brain injury. J. Neurotrauma 30, 1631�. doi: 10.1089/neu.2012.2791

Wang, F., Mullican, S. E., DiSpirito, J. R., Peed, L. C., and Lazar, M. A. (2013). Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. Proc. Natl. Acad. Sci. U.S.A. 110, 18656�. doi: 10.1073/pnas.1314863110

Wang, J., Wu, X., Simonavicius, N., Tian, H., and Ling, L. (2006). Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J. Biol. Chem. 281, 34457�. doi: 10.1074/jbc.M608019200

Wang, X., and Chan, C. B. (2015). n-3 polyunsaturated fatty acids and insulin secretion. J. Endocrinol. 224, R97–R106. doi: 10.1530/JOE-14-0581

Wang, Y.-T., Liu, C.-H., and Zhu, H.-L. (2016). Fatty acid binding protein (FABP) inhibitors: a patent review (2012-2015). Expert Opin. Ther. Pat. 26, 767�. doi: 10.1080/13543776.2016.1182500

Warden, A., Truitt, J., Merriman, M., Ponomareva, O., Jameson, K., Ferguson, L. B., et al. (2016). Localization of PPAR isotypes in the adult mouse and human brain. Sci. Rep. 6:27618. doi: 10.1038/srep27618

Watanabe, A., Toyota, T., Owada, Y., Hayashi, T., Iwayama, Y., Matsumata, M., et al. (2007). Fabp7 maps to a quantitative trait locus for a schizophrenia endophenotype. PLoS Biol. 5:e297. doi: 10.1371/journal.pbio.0050297

Watson, S.-J., Brown, A. J. H., and Holliday, N. D. (2012). Differential signaling by splice variants of the human free fatty acid receptor GPR120. Mol. Pharmacol. 81, 631�. doi: 10.1124/mol.111.077388

Wei, L., Tokizane, K., Konishi, H., Yu, H.-R., and Kiyama, H. (2017). Agonists for G-protein-coupled receptor 84 (GPR84) alter cellular morphology and motility but do not induce pro-inflammatory responses in microglia. J. Neuroinflammation 14:198. doi: 10.1186/s12974-017-0970-y

Whalen, E. J., Rajagopal, S., and Lefkowitz, R. J. (2011). Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends Mol. Med. 17, 126�. doi: 10.1016/j.molmed.2010.11.004

Wittenberger, T., Schaller, H. C., and Hellebrand, S. (2001). An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors. J. Mol. Biol. 307, 799�. doi: 10.1006/jmbi.2001.4520

Wnuk, A., and Kajta, M. (2017). Steroid and xenobiotic receptor signalling in apoptosis and autophagy of the nervous system. Int. J. Mol. Sci. 18:E2394. doi: 10.3390/ijms18112394

Wolfrum, C. (2007). Cytoplasmic fatty acid binding protein sensing fatty acids for peroxisome proliferator activated receptor activation. Cell. Mol. Life Sci. 64, 2465�. doi: 10.1007/s00018-007-7279-4

Wolfrum, C., Borrmann, C. M., Borchers, T., and Spener, F. (2001). Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proc. Natl. Acad. Sci. U.S.A. 98, 2323�. doi: 10.1073/pnas.051619898

Won, Y.-J., Lu, V. B., Puhl, H. L. III, and Ikeda, S. R. (2013). beta-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J. Neurosci. 33, 19314�. doi: 10.1523/JNEUROSCI.3102-13.2013

Woods, J. W., Tanen, M., Figueroa, D. J., Biswas, C., Zycband, E., Moller, D. E., et al. (2003). Localization of PPARδ in murine central nervous system: expression in oligodendrocytes and neurons. Brain Res. 975, 10�. doi: 10.1016/S0006-8993(03)02515-0

Wunderlich, M. T., Hanhoff, T., Goertler, M., Spener, F., Glatz, J. F. C., Wallesch, C. W., et al. (2005). Release of brain-type and heart-type fatty acid-binding proteins in serum after acute ischaemic stroke. J. Neurol. 252, 718�. doi: 10.1007/s00415-005-0725-z

Xing, G., Zhang, L., Zhang, L., Heynen, T., Yoshikawa, T., Smith, M., et al. (1995). Rat PPARgama contains A CGG triplet repeat and is prminently expressed in the thalamic nuclei. Biochem. Biophys. Res. Commun. 217, 1015�. doi: 10.1006/bbrc.1995.2871

Xu, L. Z., Sanchez, R., Sali, A., and Heintz, N. (1996). Ligand specificity of brain lipid-binding protein. J. Biol. Chem. 271, 24711�. doi: 10.1074/jbc.271.40.24711

Xu, Z. H., Buelt, M. K., Banaszak, L. J., and Bernlohr, D. A. (1991). Expression, purification, and crystallization of the adipocyte lipid-binding protein. J. Biol. Chem. 266, 14367�.

Yakunin, E., Loeb, V., Kisos, H., Biala, Y., Yehuda, S., Yaari, Y., et al. (2012). Alpha-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson’s disease. Brain Pathol. 22, 280�. doi: 10.1111/j.1750-3639.2011.00530.x

Yamashima, T. (2008). A putative link of PUFA, GPR40 and adult-born hippocampal neurons for memory. Prog. Neurobiol. 84, 105�. doi: 10.1016/j.pneurobio.2007.11.002

Yamashima, T. (2012). PUFA-GPR40-CREB signaling hypothesis for the adult primate neurogenesis. Prog. Lipid Res. 51, 221�. doi: 10.1016/j.plipres.2012.02.001

Yan, S., Elmes, M. W., Tong, S., Hu, K., Awwa, M., Teng, G. Y. H., et al. (2018). SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins. Eur. J. Med. Chem. 154, 233�. doi: 10.1016/j.ejmech.2018.04.050

Yang, Y., Tian, X., Xu, D., Zheng, F., Lu, X., Zhang, Y., et al. (2018). GPR40 modulates epileptic seizure and NMDA receptor function. Sci. Adv. 4:eaau2357. doi: 10.1126/sciadv.aau2357

Yoshimura, M., Miyata, A., Arita, K., Kurihara, T., Shioda, S., Oyoshi, T., et al. (2015). Attenuation of inflammatory and neuropathic pain behaviors in mice through activation of free fatty acid receptor GPR40. Mol. Pain 11:6. doi: 10.1186/s12990-015-0003-8

Yu, S., Levi, L., Siegel, R., and Noy, N. (2012). Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta). J. Biol. Chem. 287, 42195�. doi: 10.1074/jbc.M112.410381

Yu, Y., Zhu, M., Zhao, Y., Xu, M., and Qiu, M. (2018). Overexpression of TUSC7 inhibits the inflammation caused by microglia activation via regulating miR-449a/PPAR-gamma. Biochem. Biophys. Res. Commun. 503, 1020�. doi: 10.1016/j.bbrc.2018.06.111

Yun, S. W., Leong, C., Zhai, D., Tan, Y. L., Lim, L., Bi, X., et al. (2012). Neural stem cell specific fluorescent chemical probe binding to FABP7. Proc. Natl. Acad. Sci. U.S.A. 109, 10214�. doi: 10.1073/pnas.12008171091200817109

Zamarbide, M., Etayo-Labiano, I., Ricobaraza, A., Martinez-Pinilla, E., Aymerich, M. S., Lanciego, J. L., et al. (2014). GPR40 activation leads to CREB and ERK phosphorylation in primary cultures of neurons from the mouse CNS and in human neuroblastoma cells. Hippocampus 24, 733�. doi: 10.1002/hipo.22263

Zenker, J., Stettner, M., Ruskamo, S., Domenech-Estevez, E., Baloui, H., Medard, J.-J., et al. (2014). A role of peripheral myelin protein 2 in lipid homeostasis of myelinating Schwann cells. Glia 62, 1502�. doi: 10.1002/glia.22696

Zhang, Q., Yang, H., Li, J., and Xie, X. (2016). Discovery and characterization of a novel small-molecule agonist for medium-chain free fatty acid receptor G protein-coupled receptor 84. J. Pharmacol. Exp. Ther. 357, 337�. doi: 10.1124/jpet.116.232033

Zhang, R., Wang, Y., Li, R., and Chen, G. (2015). Transcriptional factors mediating retinoic acid signals in the control of energy metabolism. Int. J. Mol. Sci. 16, 14210�. doi: 10.3390/ijms160614210

Zhou, Y., Nie, T., Zhang, Y., Song, M., Li, K., Ding, M., et al. (2016). The discovery of novel and selective fatty acid binding protein 4 inhibitors by virtual screening and biological evaluation. Bioorg. Med. Chem. 24, 4310�. doi: 10.1016/j.bmc.2016.07.022

Zimmer, L., Delpal, S., Guilloteau, D., Aioun, J., Durand, G., and Chalon, S. (2000). Chronic n-3 polyunsaturated fatty acid deficiency alters dopamine vesicle density in the rat frontal cortex. Neurosci. Lett. 284, 25�. doi: 10.1016/s0304-3940(00)00950-2

Zimmer, L., Hembert, S., Durand, G., Breton, P., Guilloteau, D., Besnard, J. C., et al. (1998). Chronic n-3 polyunsaturated fatty acid diet-deficiency acts on dopamine metabolism in the rat frontal cortex: a microdialysis study. Neurosci. Lett. 240, 177�. doi: 10.1016/s0304-3940(97)00938-5

Zoete, V., Grosdidier, A., and Michielin, O. (2007). Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim. Biophys. Acta 1771, 915�. doi: 10.1016/j.bbalip.2007.01.007

Zolezzi, J. M., and Inestrosa, N. C. (2013). Peroxisome proliferator-activated receptors and Alzheimer’s disease: hitting the blood-brain barrier. Mol. Neurobiol. 48, 438�. doi: 10.1007/s12035-013-8435-5

Zolezzi, J. M., Santos, M. J., Bast໚s-Candia, S., Pinto, C., Godoy, J. A., and Inestrosa, N. C. (2017). PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation. Biol. Rev. Camb. Philos. Soc. 92, 2046�. doi: 10.1111/brv.12320

Keywords : lipid sensing, neuronal differentiation and development, signal transduction, free fatty acid receptor, fatty acid binding protein, peroxisome proliferator activated receptor, docosahexaenoic acid, arachidonic acid

Citation: Falomir-Lockhart LJ, Cavazzutti GF, Giménez E and Toscani AM (2019) Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors. Front. Cell. Neurosci. 13:162. doi: 10.3389/fncel.2019.00162

Received: 15 January 2019 Accepted: 08 April 2019
Published: 24 April 2019.

Gabriela Alejandra Salvador, Universidad Nacional del Sur, Argentina

Sharon DeMorrow, The University of Texas at Austin, United States
Tatsuro Mutoh, Fujita Health University, Japan

Copyright © 2019 Falomir-Lockhart, Cavazzutti, Giménez and Toscani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


2-Deoxy-D-glucose but not 2-mercaptoacetate increases Fos-like immunoreactivity in adrenal medulla and sympathetic preganglionic neurons

2-Deoxy-D-glucose (2DG) and 2-mercaptoacetate (MA) are drugs that competitively inhibit metabolism of glucose and fatty acids, respectively. Both 2DG and MA stimulate food intake. In addition, 2DG-induced glucoprivation is a known stimulus for adrenomedullary secretion. However, very little is known about the effects of MA on the sympathoadrenal system. In the present study, we examined effects of 2DG and MA on the activity of preganglionic neurons and the adrenal medulla, as indicated by expression of Fos-like immunoreactivity (Fos-li). 2DG, MA, or saline was administered using a stress-attenuated paradigm incorporating remote drug infusion. Expression of Fos-like immunoreactivity (Fos-li) was subsequently examined in the adrenal medulla and in preganglionic sympathetic neurons throughout the intermediolateral column (IML) of the thoracic and lumbar spinal cord. We found that 2DG increased Fos-li in the adrenal medulla and in the IML primarily at spinal cord segments T7-T10, where adrenomedullary preganglionic neurons reside. In contrast, MA did not induce Fos-li either in the adrenal medulla or in sympathetic preganglionic neurons at any cord level. Results support the hypothesis that decreased fatty acid oxidation is not a stimulus for adrenal medullary secretion and provide evidence for a highly selective stimulation of adrenal medullary preganglionic neurons by 2DG.