Veterinary World, Vol.2(6): 242-246 REVIEW

Appetite Regulating Hormones

Nirmala, G.C., Suchitra, B. R* and Pavankumar, K. N.

Dept. of Pharmacology and Toxicology, Veterinary College, Hebbal, Bangalore-24 * Veterinary Officer, Veterinary Dispensory, Hanabe, Bangalore Corresponding author email : [email protected]

All higher life forms exhibit a desire to eat releasing alpha-melanocyte-stimulating hormone (á- known as appetite which is felt as . Appetite is MSH) from the polypeptide preopiomelanocortin required to regulate adequate energy intake and to (POMC) or the and amphetamine regulated maintain metabolic needs. It is regulated by a close transcript (CART) in satiety center. interplay between the digestive tract, ARC integrates neural (mostly vagal) and and the . Decreased desire to eat is termed as humoral inputs such as enteropeptides including , while or hyperphagia is increased orexigenic ( and ) and anorexigenic . Dysregulation of appetite may either contribute peptides (cholecystokinin, polypeptide YY, glucagon- to or . like peptide-1, oxyntomodulin, and others) that Better understanding of appetite regulation exert a physiological role in regulating apetite and improves understanding of the etiology of debility or satiety. The peripherally (gut, adipose tissue) and obesity. Manipulation of this homoeostatic system offers centrally expressed modulators of appetitive behavior potentially useful treatments for obesity and anorexia act through specific receptors in the afferent (mostly (Druce and Bloom, 2006). vagal) nerves and hypothalamic neurons implicated in Appetite regulation adiposity signaling and regulation of food intake (Konturek et al., 2005). Appetite regulation is an immensely complex The with its key regions, including process involving: ARC, LHA and closely related PVN, serving as the 1.Hypothalamic neuropeptides feeding or hunger center, VMN acting as the satiety 2.peripheral signals like adipokines and gut hormones center and NTS conveying the peripheral signals, Hypothalamic neuropeptides particularly from the gut to the feeding centers, are Hypothalamus, posses several neuronal centers implicated in appetitive behavior. Thus, CNS receives such as that in lateral hypothalamic nuclei considered (through NTS) numerous neural impulses and to be “hunger” center and in ventromedial nuclei serving hormones from peripheral organs, especially from the as the “satiety” center. In addition, paraventricular and gastrointestinal mucosa, and fat tissue that are involved arcuate hypothalamic nuclei (ARC) are the sites where in short and long-term coordination of feeding and multiple hormones, released from the gut and adipose energy expenditure in response to constantly altered tissue, converge to regulate food intake and energy energy balance. The gut peptides signaling to the expenditure.Nucleus tractus solitarius (NTS) in the brain hypothalamus act via the ARC to mediate the appetite stem serves as gateway for neural signals from the stimulation (+) effect through the activation of gastrointestinal tract to the hypothalamic feeding centers. neurons containing neuropeptide Y (NPY) and Agouti- Also the amygdala, the cortex prefrontalis, as well as Related Peptide (AgRP) or appetite-inhibitory effects the area postrema have been held responsible for (-) via neurons containing the pro-opiomelanocortin feeding disorders and inadequate conservation or (POMC)-derived a-melanocyte stimulating hormone (a- storage of energy. MSH) and cocaine and amphetamine regulated There are two distinct types of neurons in ARC transcript (CART) peptide to hunger centers in the LHA, that are important in control of food intake; the satiety center in PVN in the medial hypothalamus (1) Neurons activated by orexigenic peptides such as (Currie et al.,2005). ghrelin that release the substances including Generally, there are two systems that operate in neuropeptide Y (NPY) and Agouti-Related Peptide the regulation of the quantity of food intake; short- (AgRP) in hunger center. term regulation, which is concerned primarily with (2) Neurons activated by anorexigenic hormones and preventing at each meal. It is regulated www.veterinaryworld.org Veterinary World Vol.2, No.6, June 2009 242 Appetite Regulating Hormones

CCK, ghrelin, and long term regulation, which is Cocaine and amphetamine regulated primarily related with the maintenance of normal transcript (CART) quantities of energy stores in the form of fat in the body. • CART is coexpressed with á-MSH in the ARC, It is regulated by hormones like insulin and leptin. also found in LHA and PVN. Neuropeptide Y (NPY) • Food deprived animals show a reduction in • NPY is part of the pancreatic polypeptide (PP) CART mRNA. family of peptides with 36 amino acids. • Peripheral administration of leptin to leptin • Bind to seven-transmembrane-domain G- deficient ob/ob mice results in a stimulation of protein-coupled receptors, designated Y -Y .·Y , CART mRNA expression. 1 6 1 • CART (1-102) and CART (82-103) icv inhibit the Y2, Y4, and Y5 receptors are found in the hypothalamus which mediates the orexigenic normal and NPY stimulated feeding response. effects of NPY. • Antiserum against CART peptide (1-102) and • NPY may inhibit the arcuate POMC neuron via CART peptide fragment (82-103) icv in rats increased hunger. ARC NPY Y1 receptors. • Hypothalamic levels of NPY reflect the body’s Orexins nutritional status. Greek- Orexis: appetite. • The levels of hypothalamic NPY mRNA and NPY i. Orexins are the novel neuropeptides play a role release increase with fasting and decrease after in the stimulation of food intake and energy refeeding. (Kirchgessner, 2002). • Repeated icv inj. of NPY into the PVN causes ii. The two highly-related peptides ( A and hyperphagia and obesity. B, or Hypocretin-1 and -2) are produced by Agouti-related peptide (AgRP) cleavage of a single precursor protein secreted • AgRP is expressed in the medial part of the ARC. by the cells in the LHA. Orexin-A is a 33-residue • The levels of AgRP mRNA are increased duuring peptide with two intramolecular disulfide fasting. linkages. Orexin-B is a linear 28-residue peptide. • Potent inhibitor of MC3R and MC4R. iii. OXA has been detected in the mucosa and • AgRP induces hyperphagia when administered neuronal plexuses of the gastrointestinal tract. icv or when over expressed in transgenic mice. iv. Plasma levels of OXA are increased during • Exogenous administration of AgRP in rodents fasting in humans and are lower in obese predisposes to high fat and high sugar intakes subjects than normal-weight people (Adam et (Loos et al., 2005). al., 2002), suggesting that peripheral OXA • Induced selective ablation of AgRP-expressing modulates food intake as an orexigenic peptide. neurons in adult mice results in acute reduction Peripheral signals controlling appetite of feeding (Gropp et al., 2005). Hormones of adipose tissue (Adipokines) The melanocortin system • Insulin • The anorexigenic neurons in the arcuate • Adiponectin nucleus produce á-MSH from the polypeptide • Leptin precursor POMC. Hormones of GIT. • They bind to melanocortin receptor family of • Ghrelin which MC3R and MC4R are important. • Cholecystokinin • POMC mRNA levels are reduced in fasted • Glucagon like peptide-1 (GLP-1) animals and increased by exogenous • Oxyntomodulin administration of leptin, or restored by refeeding • PYY3-36 after 6h. Insulin • MC3R and MC4R are the receptors found in the ARC, VMH and PVN which play a role in energy • Insulin is poudeced by the pancreas in relation homeostasis. to the adiposity and blood glucose levels. • The MC3R/MC4R antagonist, AgRP is able to • It acts on the insulin receptors in the ARC of increase food intake in MC4R deficient mice. hypothalamus to inhibit the eating behavior: • Lack of MC4R leads to hyperphagia and obesity - inhibits the release of NPY/AgRP. in rodents. - stimulate á-MSH and CART. • The main endogenous ligand for the MC3R/ • Insulin applied intra-cerebro-ventricularly (icv) MC4R is á-MSH. inhibits food intake and body weight in rats. www.veterinaryworld.org Veterinary World Vol.2, No.6, June 2009 243 Appetite Regulating Hormones

• icv administration of insulin antibodies increased “leptin/ghrelin tango” operating along the brain-gut axis, food intake and body weight. leptin belongs together with insulin to a “lipostat” Adiponectin substances that play a role in adiposity signaling. Insulin, like leptin, is thought to inhibit NPY/AgRP • It is a peptide hormone (adipokine) with 224 neurons in ARC region of the hypothalamus and reduce amino acids secreted by the white adipose tissue food intake. This is supported by the observations that (Trayhurn,2005). insulin applied intra-cerebro-ventricularly (icv) inhibits • Peripheral administration of adiponectin results in the attenuation of body-weight gain without food intake. Accordingly icv administration of insulin affecting food intake. antibodies increased food intake and body weight (Air • Increases oxygen consumption by inducing the et al., 2002). Thus, leptin-like insulin, represents expression of gene c-fos in the PVN and involving adiposity signal inhibiting food intake by interacting with melanocortin system. hypothalamic receptors activated through POMC and • Increased after food restriction in rodents and CART neuronal pathways stimulating satiety center, after induced by a calorie-restricted and reducing the activity of NPY/AgRP neurons driving diet. the appetitive behavior. Leptin Peptide YY3–36 (PYY) leptos: thin. Leptin is an anorexigenic adipokine • A peptide hormone (34 amino acids) that is with 167 amino acids. secreted postprandially, in respose to food Production sites: entering from the stomach. a. adipose tissue • Endocrine L cells lining the ileal and colon b. nonadipose tissue:stomach, placenta, skeletal mucosa (Judith Korner et al., 2003). muscle and mammary epithelium • PYY3-36, acts via Yl, Y2, Y3 and Y5 receptors. • Combine with the Ob-R on afferent vagal nerves • Peripheral administration: Decrease appetite and and directly on the ARC to enhance satiety. cause weight loss by inhibiting ARC expressions • Inhibits the expression of orexigenic NPY/AgRP of NPY/AgPR (Hagan, 2002). hypothalamic neurons. • Cetral administration: stimulate food intake by • Also stimulates the anorexigenic POMC neurons enhancing the expression of NPY/AgRP. in ARC. Ghrelin Actions of leptin ghre: grow. Ghrelin is a potent orexigenic 1. Thermogenesis 2. Decrese in Food intake hormone with 28 amino acids secreted from X/A cells Thermogenesis in the fundus mucosa of empty stomach (Rindi et al., Stimulate the transcription of mitochondrial 2002). uncoupling protein (UCP) or thermogenin, which forms Biological activities: a channel in the inner mitochondrial membrane that 1. Stimulation of GH secretion through GHS-R. allows protons to reenter the mitochondrial matrix 2. Regulation of energy balance/appetite. without passing through the ATP synthase complex. 1.Stimulation of growth hormone secretion: Ghrelin, This permits the continual oxidation of fuel (faty acids as the ligand for the growth hormone secretagogue in an adipocyte) without ATP synthesis, dissipating receptor, potently stimulates the secretion of the growth energy as heat and consuming dietary calories or hormone. The ghrelin signal is integrated with that of stored fats in potentially very large amounts ( Nelson the growth hormone-releasing hormone and and Cox 2005). somatostatin to control the timing and magnitude of Decrease in food intake: growth hormone secretion. • Combine with the Ob-R on afferent vagal nerves 2.Regulation of energy balance: In rodents and and directly on the ARC to enhance satiety. humans, ghrelin functions to increase hunger through • Inhibits the expression of orexigenic NPY/AgRP its action on the hypothalamic feeding centers. The hypothalamic neurons. plasma ghrelin concentrations increase during fasting. • Also stimulates the anorexigenic POMC neurons Humans injected with ghrelin reported sensations of in ARC. intense hunger. Ghrelin also appears to suppress fat Leptin - insulin lipostat utilization in the adipose tissue, which is somewhat Although there is rather low local expression of paradoxical considering that the growth hormone has leptin in the stomach, probably responsible for local the opposite effect. Overall, ghrelin seems to be one of antagonism of gastric release of ghrelin and named several hormonal signals that communicate the state www.veterinaryworld.org Veterinary World Vol.2, No.6, June 2009 244 Appetite Regulating Hormones of energy balance in the body to the brain. and ceiis in peripheral nerves and neurons of Regulation of appetite the brain.

• The primary hypothalamic target for ghrelin are • Acts via CCKi receptors on vagal afferent nerves. neurons in ARC that express and release NPY • Hormone exists in the mucosa and circulation in and AgRP in the PVN and LHA to mediate several molecular forms such as CCK-8, CCK- orexigenic effect in the brain. 33, CCK-39 and CCK-58. • It may also inhibit the neurons in the ARC that All these molecular forms derive from a single contain POMC-derivative a-MSH that mediate CCK gene through posttranslational processing and the anorexigenic effect in the PVN (Currie et al., have the same C-terminal five amino acid sequence 2005). (Rehfeldt, 2004). Other effects of ghrelin include stimulation of CCK is the likely candidate for the physiological gastric emptying and a variety of positive effects on mediation of short-term inhibition of food intake. It cardiovascular function (e.g. increased cardiac output). cooperates with signals originating from the It is not yet clear whether the cardiovascular effects mechanoreceptors of the gut that are generated by the are due to a direct effect of ghrelin or an indirect effect distention of the gut and transmitted to the brain through of ghrelin’s ability to stimulate growth hormone vagal afferents. This is in keeping with earlier findings secretion. The concentration of ghrelin in blood peaks that sub-diaphragmatic vagotomy abolishes just before a meal and drops suddenly just after the anorexigenic activity of exogenous CCK and, as we meal. found it for the first time and the blockage of CCK[ Prader-Willi syndrome: It is a disorder relevant to receptors with loxiglumide abolishes the anorexigenic ghrelin. Affected patients develop extreme obesity effects of both exogenous and endogenous hormone. associated with an uncontrollable and voracious The clinical usefulness of CCK as an anti-obesity, appetite. The plasma ghrelin levels are exceptionally appetite reducing agent was found, however, to be high in comparison to patients similarly obese due to transient due to the development of tolerance to CCK other causes. and its analogs (Crawly and Beinfeld, 1983). Ghrelin as a drug target:People who lose weight have Furthermore, even removal of gene for CCKi receptors, higher blood levels of ghrelin, than they did when they (CCKi receptor knockout mouse) failed to increase the were fat. This also supports the concept that the body food intake, but resulted in the lack of the sensitivity of tends to maintain its ideal weight and when one loses these animals to anorexigenic action of exogenous weight, the body should produce more ghrelin to CCK. Since CCK only intermittently preserves its stimulate to regain the lost weight. Therefore ghrelin anorexigenic activity between injections of exogenous makes one fatter by causing hunger to eat more and CCK, compensatory overeating occurs, so it is unlikely slowing to burn fewer calories. that this peptide could be useful in anti-obesity therapy. A rise or fall in ghrelin is not observed in patients Glucagon-like peptide-1 (GLP-1) who had gastric bypass surgery, before or after they • Glucagon-like peptide-1 (GLP-1) is a eat. Their levels of ghrelin remain low all the time. This anorexigenic peptide secreted by endocrine L- shows that stomach cells produce ghrelin only when cells in the ileal and colonic mucosa in response food passes into the stomach. An empty stomach to food intake. causes stimulation of ghrelin secretion while food in • Increase satiety and decrease food intake in the stomach stops production of ghrelin. However, when normal-weight subjects, diabetes patients and no food enters the stomach for a long time, stomach obese subjects (Gutzwiller et al., 1999). cells stop producing ghrelin and a person stops being • GLP-1 reduces the postprandial demand of hungry. That is why when it is long past normal mealtime insulin to maintain euglycemia after a meal a person stops feeling hungry. So drugs that can block (Imeryuz et al., 1997). ghrelin will be very effective to overcome obesity without • GLP-1 on gastrointestinal functions are mediated much disturbance in the physiological homeostasis of through its distinct receptors on vagal nerves. our body. Intense research is going on in this regard Oxyntomodulin (OXM) for a breakthrough drug in obesity (Madan, 2005). • Oxyntomodulin (OXM) is produced by the same Cholecystokinin (CCK) L-cells as GLP-1 in the distal portion of the gut Among the anorexigenic peptides, the first and also in the brain. recognized inhibitor of food intake in rodents and then • It is a 37 amino acid peptide released after in humans was cholecystokinin (CCK). ingestion of meal. • Secreted by duodeno-jejunal endocrine I cells • Involved in the short-term suppression of food www.veterinaryworld.org Veterinary World Vol.2, No.6, June 2009 245 Appetite Regulating Hormones

intake. 4701. • The mechanism of anorexigenic action of OXM 4. Crawley, J.N. and Beinfeld, M.C. (1983): Rapid is not known but it may involve the suppression development of tolerance to the behavioural actions of plasma ghrelin levels (Cohen et al., 2003). of cholecystokinin. Nature, 302: 703-705. • OXM, act through GLP-1 receptors. 5. Currie, P. J., Mirza, A., Fuld, R., Park, D. and Vasselli, J. R. (2005): Ghrelin is an anorexigenic and metabolic Obestatin signaling peptide in the arcuate and paraventricular Latin: Obedere- to devour, Statin- suppression. nucleus. Am. J. Physiol. 289: R353-353. Ghrelin, a circulating appetite-inducing hormone, 6. Druce, M. and Bloom, S.R. (2006): The regulation of is derived from a prohormone by posttranslational appetite. Arch. Dis. Child. 91:183-7. 7. Gropp, E., Shanabrough, M., Borok, E., Xu, A.W., processing. On the basis of the bioinformatic prediction Janoschek, R., Buch, T., Plum, L., Balthasar, N., that another peptide also derived from proghrelin exists, Hampel, B., Waisman, A., Barsh, G.S., Horvath, T.L. they have isolated a hormone from rat stomach and and Bruning, J.C. (2005): Agouti-related peptide- named it obestatin-a contraction of obese, from the expressing neurons are mandatory for feeding. Nat. Latin “obedere,” meaning to devour, and “statin,” Neurosci. 8:1289-91. denoting suppression. Contrary to the appetite- 8. Gutzwiller. J., Goke, B., Drewe, J., Hildebrand, P., stimulating effects of ghrelin, treatment of rats with Ketterer, S., Handschin, D., Winterhalder, R., Conen, obestatin suppressed food intake, inhibited jejunal D. and Beglinger, C. (1999): Glucagon-like peptide: A contraction, and decreased body-weight gain. potent regulator of food intake in humans. Gut, 44: 81- 86. Obestatin bound to the orphan G protein-coupled 9. Hagan, M. M. (2002): Peptide YY: a key mediator of receptor GPR39. Thus, two peptide hormones with orexigenic behavior. Peptides, 23: 377-382. opposing action in weight regulation are derived from 10. Imeryuz, N., Yegen, B.C., Bozkurt, A., Coskun, T., the same ghrelin gene. After differential modification, Villanueva, P., and Ulusoy, N.B. (1997): Glucagon- these hormones activate distinct receptors (Zhang et like peptide-1 inhibits gastric emptying via vagal al., 2005). afferent-mediated central mechanisms. Am. J. Conclusion Physiol., 273: 920-927. 11. Korner, J. and Leibel, R. L. (2003): To Eat or Not to Eat The better understanding of hormonal control of - How the Gut Talks to the Brain. N. Engl. J. Med. appetite improves understanding of the etiology of 349:926-928. debility or obesity. Manipulation of this homeostatic 12. Kirchgessner, A. L. (2002): Orexins in the brain-gut system by pharmacological intervention offers axis. Endocrinol. Rev. 23: 1-15. potentially useful treatments for anorexia and obesity. 13. Konturek, P.C., Konturek, J.W., Czesnikiewicz, G. M., Brzozowski, T. and Sito, E. (2005): Neuro-hormonal References control of food intake; basic mechanisms and clinical 1. Adam, J. A., Menheere, P.P., van Dielen, F.M., Soeters, implications. J. Physiol. Pharmacol. 56:5-25. P.B., Buurman, W.A. and Greve, J.W.(2002): 14. Loos, R.J., Rankinen, T., Rice, T., Rao, D.C., Leon, Decreased plasma orexin-A levels in obese A.S., Skinner, J.S., Bouchard, C. and Argyropoulos, individuals. Int. J. Obes. Relat. Metab. Disord. 26: 274- G. (2005): Am. J. Clin. Nutr. 82:1097-101. 276. 15. Madan, A. K. (2005): Ghrelin: A potential drug target 2. Air, E.L., Benoit, S.C., Smith, B., Clegg, D.J. and for obesity. Ind. J. Pharmacol., 37; 133-134. Woods, S.C. (2002): Acute third ventricular 16. Nelson, D.L. and Cox, M.M. (2005): Lehninger administration of insulin decreases food intake in two Principles of Biochemistry. 4th edn. W.H. Freeman and paradigms. Pharmacol. Biochem. Behav.72: 423-429. Company, New York, pp 910-912. 3. Cohen, M.A., Ellis, S.M. and Le Roux, C.W. (2003): 17. Rehfeldt, J.F. (2004): Clinical endocrinology and Oxyntomodulin suppresses appetite and reduces food metabolism. Cholecystokinin. Best. Pract. Res. Clin. intake in humans. J. Clin. Endocrinol .Metab. 88: 4696- Endocrinol. Metab. 18: 569-586.

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