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Ghrelin - an orexigenic hormone
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Ghrelin - an orexigenic hormone

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  • 1. Dr. Amita k. Mevada Tutor and 2nd year resident, Physiology Department, B.J.Medical college.
  • 2.  Ghrelin has emerged as the first identified circulating hunger hormone.  Ghrelin is both a hormone in the endocrine system and a neurotransmitter in the nervous system.  It is known as the  circulating orexigen, or  appetite-regulating hormone or appetite enhancing hormone.  growth hormone secretagogue or  motilin-related peptide
  • 3.  The discovery of ghrelin followed after the discovery of the growth hormone secretagogue type 1A receptor in 1996 and was reported by Masayasu Kojima and colleagues in 1999.  The name is based on its role as a growth hormone-releasing peptide, with reference to the Proto-Indo-European root ghre, meaning to grow.(Growth Hormone Release Inducing = Ghrelin)
  • 4.  It is encoded by the GHRLgene.  The mRNA from the GHRL gene codes for a 117 amino acid peptide called preproghrelin, containing 4 exons.  The signalling peptide molecule of this larger precursor is cleaved to produce proghrelin(94 aa).  Proghrelin is cleaved in two to produce the 28 amino acid peptide ghrelin (unacylated) and C-ghrelin (of which obestatin is presumed to be a cleaved form).
  • 5. GIT:  Ghrelin is produced mainly by P/D1 cells, lining the fundus of the human stomach, that contain granules filled with ghrelin.  Also by epsilon cells of the pancreas that stimulates hunger.  It has been found that during fetal development, the ghrelin concentration in the pancreas is six to seven times higher than in the stomach. In fetus, the stomach may not be the major source for circulating ghrelin.  The number of epsilon cells increases during fetal development, and close to birth they begin to localise at the periphery of the developing islets.  In rodents, X/A-like cells produce ghrelin.
  • 6.  Aside from the stomach and pancreas in adults, ghrelin cells are also found in the duodenum, jejunum, i leum, and colon, with ghrelin concentration decreasing from the duodenum to the colon.
  • 7. Hypothalamic arcuate nucleus and the anterior pituitary gland:  In the hypothalamic arcuate nucleus, ghrelin primarily induces the release of appetite- stimulating neurons  In the anterior pituitary gland ghrelin acts on GH- releasing somatotrophs and caused the immediate secretion of growth hormone (GH) by increasing their intracellular Ca2+ concentration. Also secreted by the lungs, gonads, adrenal cortex, glomeruli of the kidney and syncytio- trophoblast cells of placenta.
  • 8. 'Ghrelin' usually refers to the octanoylated form of ghrelin (acyl ghrelin). This is the 28 amino acid peptide sequence with an octanoylation on the third amino acid (serine). About 20% of ghrelin is octanoylated
  • 9.  The octanoylation is performed by the ghrelin O- acyltransferase (GOAT) protein (a member of the membrane-bound O-acyltransferase family of proteins), located in the stomach and pancreas.  Only this n-octanoylated form is active and able to bind to GHS-R receptor to stimulate GH secretion and is thus known as the acyl ghrelin or active form of ghrelin.
  • 10. The non-octanoylated form is known as desacyl ghrelin or the inactive form, and does not activate GHSR1a and thus does not release growth hormone like acyl ghrelin; however studies have shown it has its own effects.
  • 11. The normal ghrelin concentration of plasma samples in humans  total ghrelin= 100–150 fmol/ml  n-octanoyl ghrelin= 10–20 fmol/ml
  • 12.  The ghrelin acts by binding to the GHSR1a(growth hormone secretagogue receptor) splice-variant of this receptor.  GHSR1a is a G protein-coupled receptor with seven transmembrane domains.  Ghrelin after binding to the GHSR1a  activates phospholipase C1 generates IP3 and diacylglycerol, resulting in an increase in the intracellular Ca2+ concentration  stimulates the release of GH.
  • 13.  Receptors for ghrelin are located primarily in the lateral hypothalamus and pituitary, it is also found in various peripheral organs, such as the stomach, pancreas, thymus, gonads, thyroid, heart , lung, liver and vagal afferent endings throughout the gastro-intestinal tract.  It is also found in the hippocampus, which implies a possible link between ghrelin and memory function.  The diversity of ghrelin receptor locations suggests ghrelin has widespread and diverse biological functions.
  • 14.  The hypothalamus is a region of the brain that strongly controls feeding patterns and appetite.  Ghrelin-containing neurons are found primarily in hypothalamic arcuate nuclei (ARC) and hypothalamic paraventricular nuclei (PVN), although the ARC is the primary site of ghrelin‟s activity.
  • 15.  In the ARC, ghrelin stimulates the release of neuropeptide Y (NPY) and agouti- related protein (AgRP)-expressing neurons (increase the appetite), and it suppresses the release of proopiomelanocortin (POMC) neurons (decrease the appetite).
  • 16.  In the PVN, ghrelin neurons send efferent fibers onto NPY neurons, which suppress the release of GABA and in turn stimulate corticotrophin-releasing hormone-expressing neurons, leading to adrenocorticotropic hormone (ACTH) and cortisol release.  ACTH and cortisol have numerous effects in the body, one of which includes increasing blood sugar levels.
  • 17. Ghrelin and synthetic ghrelin mimetics (the growth hormone secretagogues) increase food intake and increase fat mass by an action exerted at the level of the hypothalamus. Ghrelin-responsiveness of these neurons is both leptin- and insulin-sensitive.
  • 18.  There is also strong evidence that ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechano-sensitivity of gastric vagal afferents, making them less sensitive to distension resulting in over eating.  The vagus nerve is a major pathway in conveying ghrelin‟s signals from the stomach to the brain.
  • 19. Ventromedial nucleus satiety centre (lesion leads to hyperphagia) Lateral nucleus Hunger / feeding centre. (lesion leads to anorexia) N.arcuate – pivotal role in the integration of signals regulating appetite
  • 20.  Recently ghrelin has also been shown to act on regions of the brain involved in reward processing such as the amygdala.  It activates the mesolimbic cholinergic- dopaminergic reward link, a circuit that communicates the hedonic and reinforcing aspects of natural rewards, such as food, as well as of addictive drugs, such as ethanol.  Indeed, central ghrelin signalling is required for reward from alcohol and palatable/rewarding foods.
  • 21. Ghrelin augments the firing rate of NPY, AgRP, GABA neurons and augments the production of AgRP/NPY (neurotransmitters). Subsequent GABA release reduces the firing rate of POMC neurons (hyperpolarization). Result: dominant activity of orexigenic neurons
  • 22.  Obestatin is a putative hormone that was described, in late 2005.  Obestatin was originally identified as an anorectic peptide.  Both obestatin and ghrelin are encoded by the same gene; the gene's product breaks into two smaller peptides, ghrelin and obestatin.  The purpose of this mechanism that produces two hormones with opposing effects remains unclear, however may explain earlier findings, namely that removing the ghrelin gene from mice did not significantly reduce their appetite.  Obestatin has been shown to antagonise growth hormone secretion and food intake induced by ghrelin
  • 23.  Ghrelin levels increase before meals and decrease after meals.  It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels.
  • 24. (1) Appetite Inducer  It is termed the „hunger hormone / orexigenic hormone. ‟ because it stimulates appetite, increases food intake and promotes fat storage.  Ghrelin has a peripheral appetite modulatory effect on satiety by affecting the mechanosensitivity of gastric vagal afferent.  Ghrelin also appears to suppress fat utilization in adipose tissue.  Blood levels of ghrelin rise during fasting, peak just before eating, and then fall rapidly after a meal, suggesting a possible role in stimulating feeding.
  • 25.  When administered to humans, ghrelin increases food intake by up to 30% by circulating in the bloodstream at the hypothalamus, an area of the brain crucial in the control of appetite.  Ghrelin does not increase meal size, only meal number.
  • 26.  Ghrelin injections also increase an animals‟ motivation to seek out food, behaviours including increased sniffing, foraging for food, and hoarding food.  Ghrelin also readies the body for the incoming nutrients by stimulating gastrointestinal motility and gastric acid secretions (acting through vagus nerve which also has GHS- R1a receptor),as does motilin  called as motilin-related peptide.
  • 27. (2) Body Weight Regulation  Studies have shown that ghrelin levels are negatively correlated with weight.  When a person loses weight, their ghrelin levels increase, which causes increased food consumption and weight gain.  Conversely, when a person gains weight, their ghrelin levels drops, leading to a decrease in food consumption and weight loss.  This data suggests that ghrelin functions as an adiposity signal, acts as a body weight regulator, continually keeping one‟s body weight and energy stores in check.
  • 28. (3) Gastrointestinal tract  Ghrelin has been proposed as a hormone which promotes intestinal cell proliferation and inhibits its apoptosis during inflammatory states and oxidative stress.  It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms, thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions, (colitis, ischemia reperfusion injury and sepsis).
  • 29.  Ghrelin decreases pro-inflammatory cytokines in sepsis by means of activation of the vagus nerve. This is so since the vagus mediator, acetylcholine, has potent anti-inflammatory actions  It has also been shown to have regenerative capacity and is beneficial in case of mucosal injury to the stomach. But Ghrelin also appears to promote gastrointestinal and pancreatic malignancy.
  • 30. (4) Ghrelin also stimulates the release of growth hormone from the pituitary gland, and causes the build-up of muscle. (5) Lung development  Ghrelin protein has been found in the endocrine cells of the fetal lung in decreasing amounts from the embryonic to late fetal periods and promotes growth.  Its expression was shown to be maintained in newborns and children under 2 years, but it was found to be virtually absent in older individuals
  • 31. (6) Learning and memory  Animal models indicate that ghrelin may enter the hippocampus from the bloodstream, altering nerve- cell connections, and so enhancing learning and memory.  It is suggested that learning may be best during the day and when the stomach is empty, since ghrelin levels are higher at these times.
  • 32.  Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning.
  • 33. (7) Stress-induced depression  The hormone might help defend against symptoms of stress-induced depression and anxiety.  The researchers stressed both wild-type mice and altered mice that were unable to respond to ghrelin, by exposing them to very aggressive “bully” mice. .
  • 34.  They found that, after experiencing stress, both types of mice had significantly elevated levels of ghrelin that persisted at least four weeks after their last defeat encounter.  The altered mice, however, displayed significantly greater social avoidance than their wild-type counterparts, indicating an exacerbation of depression-like symptoms. They also ate less than the wild-type mice.
  • 35. (8) Sleep duration  An inverse relationship between the hours of sleep and blood plasma concentrations of ghrelin exists  As the hours of sleep increase, ghrelin concentrations lower, thereby potentially reducing appetite and avoiding potential obesity.  Short sleep duration is associated with high levels of ghrelin and obesity.  "When sleep is restricted to four hours a night, ghrelin levels go up and leptin levels go down," says National Sleep Foundation spokesperson William Orr, PhD, president and CEO of the Lynn Health Science Institute.
  • 36. (9) The presence of the Ghrelin-R on pancreatic β-cells already suggested a role for ghrelin in the function of the β- cell, leading to the hypothesis that ghrelin also has a regulatory role in insulin secretion. (10) Regarding the reproductive system, ghrelin has inhibitory effects on GnRH secretion from the hypothalamus, thus appearing to potentially cause decreased fertility.
  • 37. (11) Ghrelin also has protective effects on the cardiovascular system.  An intravenous bolus of human ghrelin decreased mean arterial pressure without changing the heart rate.  Ghrelin also increased the cardiac index and stroke volume indices.
  • 38.  Ghrelin levels are primarily regulated by food intake.  Levels of ghrelin in the blood rise just before eating and when fasting (in line with increased hunger) , with the timing of these rises being affected by our normal meal routine.  Hence, ghrelin is thought to play a role in mealtime „hunger pangs‟ and the need to begin meals.  Eating reduces concentrations of ghrelin.  Levels of ghrelin are lower in individuals with a higher body weight compared to lean individuals, which suggests ghrelin could be involved in the long-term regulation of body weight.
  • 39.  Ghrelin level increases 1-2 hr prior to meal, max just before eating and decreases dramatically within 1 hr after meal
  • 40.  Different nutrients slow down ghrelin release to varying degrees; carbohydrates and proteins restrict the production and release of ghrelin to a greater extent than fats.  Somatostatin also restricts ghrelin release, as well as many other hormones released from the digestive tract.
  • 41. Factors influencing Ghrelin secretion ↑ Ghrelin: ↓ Ghrelin: leptin Food intake Fasting Glucose/lipid GHRH, thyroid hormone Insulin, Sleep deprivation Somatostatin Lean people/ low BMI Obese people/high BMI Anorexia nervosa PYY / PP
  • 42. Incresed ghrelin:-  Dieting: Ghrelin levels increase after dieting, which may explain why diet-induced weight loss can be difficult to maintain.
  • 43.  Prader-Willi syndrome is a complex genetic disorder characterized by hyperphagia, mental retardation, short stature, muscular hypotonia. Patients may have severe obesity and learning difficulties. Unlike more common forms of obesity, circulating ghrelin levels are high in Prader-Willi syndrome patients and start before the development of obesity. Visceral adiposity and insulin resistance are reduced in PWS, which might lead to hyperghrelinemia, this ghrelin may contribute to their increased appetite and body weight.
  • 44.  Ghrelin levels are high in the eating disorder, anorexia nervosa.  Anorexia nervosa is characterized by an obsessive fear of gaining weight and a distorted self image, the compulsion of course, is to starve themselves.  Ghrelin levels are also high in cancer-induced cachexia  This may be the body‟s way of making up for weight loss by stimulating food intake and fat storage.
  • 45.  The level of ghrelin increases during the time of day from midnight to dawn in thinner people which suggests there is a flaw in the circadian system of obese individuals. Short sleep duration may also lead to obesity, through an increase of appetite via hormonal changes. Lack of sleep produces ghrelin, which stimulates appetite and creates less leptin.
  • 46. Decresed ghrelin:- Obesity:  One would expect higher levels in people with obesity. However, ghrelin levels are usually lower in people with higher body weight compared to lean people which suggests ghrelin is not a cause of obesity.  Obese people are actually more sensitive to the hormone.  Serum ghrelin levels are inversely related to changes of body weight.
  • 47. Gastric bypass surgery, which involves reducing the size of the stomach, is considered to be the most effective treatment for severe, life-threatening obesity. Patients who lose weight after bypass surgery have been found to have lower ghrelin levels than those who lose weight by other means such as diet and exercise.
  • 48.  physical restriction of the stomach (gastric pouch)  The reduction of nutrient digestion and absorption  suppression of plasma ghrelin by gastric bypass surgery  can contribute to the more efficacy of this procedure as weight reduction therapy.
  • 49.  This might be related to the finding that some patients develop some level of cognitive impairment after gastric bypass surgery because of the significant role of ghrelin in cognitive function.  Ghrelin through its receptor increases the production and release of dopamine in the substantia nigra, a region of the brain where dopamine cell degeneration leads to Parkinson's disease. Hence ghrelin may find application in slowing down the onset of Parkinson's disease.  In fact, animal models of colitis, ischemia reperfusion, and sepsis-related gut dysfunction have been shown to benefit from therapeutic doses of ghrelin.
  • 50.  Capromorelin (RQ-00000005):  increase body weight without increasing body fat and to improve motility and appetite in the elderly, it has the potential for many uses, including GERD  Anamorelin (ONO-7643):  orally active  Used in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia.  It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH).  Ulimorelin (TZP-101)  accelerates gastric emptying and improves upper gastrointestinal symptoms in diabetic patients with gastroparesis.  Tabimorelin hemifumarate  orally active  These all drugs are under clinical trial in phase 2 and 3
  • 51.  Cortistatin-8:  lacks the ability to bind somatostatin receptors but retains ghrelin receptor binding.  Acts as a ghrelin receptor antagonist; counteracts the response of ghrelin on gastric acid secretion.  YIL 781:  Ghrelin receptor antagonist (GHS-R1a).  Displays no significant affinity for the motilin receptor.  Blocks the effects of ghrelin on insulin secretion both in vivo and in vitro. Improves glucose homeostasis in vivo.
  • 52.  Specifically, Zorrilla et al. developed a vaccination strategy designed to neutralize the actions of the orexigenic hormone ghrelin  In a recent publication from the Proceedings of the National Academy of Sciences, Zorilla and colleagues addressed this novel approach of vaccinating rats against their own endogenous ghrelin.
  • 53.  The vaccine uses the immune system, specifically antibodies, to bind to selected targets, directing the body's own immune response against them.  The vaccines consisted of molecules mimicking the structure of the acylated form of ghrelin and, as intended, led to the production of specific anti-ghrelin antibodies that specifically recognized n-octanoyl- modified ghrelin.  This prevents ghrelin from reaching the central nervous system, increase their energy expenditure and decrease their food intake, thus producing a desired reduction in weight gain.
  • 54.  Guyton and Hall. Textbook of Medical Physiology, 12th Edition  Endocrine physiology, Third Edition. Patricia E. Molina, MD, PhD  Indu Khurana. Textbook of Medical Physiology, 1st Edition  Ganong‟s Review of Medical Physiology - 23rd Ed  Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005; 85:495.  Zorrilla et al. Vaccination against weight gain. Proceedings of the National Academy of Sciences. (2006) 103 (35):13266- 13231  www.ncbi.nlm.nih.gov/pubmed/17035664: Prospects for an anti-ghrelin vaccine to treat obesity.  www.sciencedaily.com/releases/2011/06/110606092537:Anti- obesity vaccine reduces food consumption in animals