Gut Hormones and Appetite Control

Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut–brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity. Many peptides are synthesized and released from the gastrointestinal tract. Although their roles in the regulation of gastrointestinal function have been known for some time, it is now evident that they also physiologically influence eating behavior. Our understanding of how neurohormonal gut–brain signaling regulates energy homeostasis has advanced significantly in recent years. Ghrelin is an orexigenic peptide produced by the stomach, which appears to act as a meal initiator. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, and cholecystokinin. Recent research suggests that gut hormones can be manipulated to regulate energy balance in humans, and that obese subjects retain sensitivity to the actions of gut hormones. Gut hormone-based therapies may thus provide an effective and well-tolerated treatment for obesity. The prevalence of obesity in adults has increased by over 75% worldwide since 1980.1Flegal K.M. Epidemiologic aspects of overweight and obesity in the United States.Physiol Behav. 2005; 86: 599-602Crossref PubMed Scopus (154) Google Scholar Given that obesity is causally associated with cardiovascular disease, type 2 diabetes, hypertension, stroke, obstructive sleep apnoea, and certain cancers, this has translated into healthcare costs of over half a billion pounds every year in the United Kingdom alone.2Bourn J. Tackling obesity in England.Report by the comptroller and auditor general. The Stationery Office, House of Commons, England2001Google Scholar Obesity is not only a problem in the developed world, but is set to overtake infectious diseases as the most significant contributor to ill health worldwide, and has been classified as an epidemic by the World Health Organization.3WHOObesity: preventing and managing the global epidemic.Report of a WHO consultation on obesity. Author, Geneva, Switzerland2004Google Scholar The increasing prevalence of obesity in younger generations suggests that this epidemic will continue to worsen.Public health initiatives have failed to reverse the rising incidence of obesity. Medical and behavioral interventions, with the exception of bariatric surgery, have limited success, in general promoting no more than 5%–10% reduction in body weight. Furthermore, weight regain, even after this modest weight loss, is almost universal.4Yanovski S.Z. Yanovski J.A. Obesity.N Engl J Med. 2002; 346: 591-602Crossref PubMed Scopus (458) Google Scholar There are good reasons for this, which can be understood by examining the homeostatic mechanisms that defend body weight. In attempting to lose weight by dieting, the body faces compensatory “starvation” signals from the gut and adipose tissue, all with a single aim of promoting hunger and storage of calories as fat. The notion that energy balance is tightly regulated to defend a “set-point” body weight may seem contradictory to our common experience that food intake varies widely day to day. Such marked diurnal variation may have led to the popular belief, particularly among lean individuals, that regulation of body weight is largely a matter of willpower. It is hard to imagine such a view of the regulation of any similarly important aspect of physiology, for example blood pressure, persisting for so long. In fact, when examined over the longer term, energy balance is extremely finely regulated.During the evolution of the homeostatic mechanisms regulating body weight, food shortage has been the norm. The mechanisms that have allowed the human race to survive famine may not be so well suited to the current situation. The increasing incidence of obesity coincides with widespread availability of highly palatable food of high energy density that can be obtained without having to expend energy. This review will focus on the peptide hormone signals from the gut that communicate the status of body energy stores to the brain and the brain centers on which they act. These regulatory systems are not only of academic interest, but are likely to underpin any future strategy to tackle obesity, by providing drug targets for the holy grail of a safe sustainable weight loss.Currently available drug therapies have limited efficacy and considerable side effects. Two agents are currently licensed for weight loss. Orlistat inhibits dietary fat absorption, resulting in an additional loss of 3% to 4% of body weight over diet alone in a 2-year period.5Curran M.P. Scott L.J. Spotlight on orlistat in the management of patients with obesity.Treat Endocrinol. 2005; 4: 127-129Crossref PubMed Scopus (3) Google Scholar It also results in deficiency of fat-soluble vitamins and fairly dramatic gastrointestinal side effects, which make it unacceptable for many patients. Sibutramine is a serotonin and norepinephrine reuptake inhibitor that acts in the central nervous system (CNS) to reduce energy intake and increase energy expenditure. It has similar efficacy to orlistat but also increases incidence of tachycardia and hypertension. Both of these drugs only have data supporting treatment for up to 2 years. In the United Kingdom, national prescribing guidelines generally recommend withdrawal after 1 year, after which significant weight regain is common.6Finer N. Pharmacotherapy of obesity.Best Pract Res Clin Endocrinol Metab. 2002; 16: 717-742Abstract Full Text PDF PubMed Scopus (44) Google ScholarSeveral newer antiobesity therapies targeting CNS receptors are in development or have recently been marketed. Among these is rimonabant, a cannabinoid CB1 receptor antagonist. This appears to be an effective weight-loss agent but is associated with high levels of drop-out due to anxiety and depression.7Van Gaal L.F. Rissanen A.M. Scheen A.J. Ziegler O. Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.Lancet. 2005; 365: 1389-1397Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar The CB1 receptor has a very wide distribution, both in the CNS and the periphery, suggesting a wide range of physiologic functions.8Howlett A.C. The cannabinoid receptors.Prostaglandins Other Lipid Mediat. 2002; 68-69: 619-631Crossref PubMed Scopus (174) Google Scholar There is evidence that cannabinoids have neuroprotective, anti-inflammatory and antiatherosclerotic actions, and concerns have been raised that rimonabant may promote diseases including multiple sclerosis and ischemic heart disease.9van O.B. Killestein J. Polman C. Effect of rimonabant on weight reduction and cardiovascular risk.Lancet. 2005; 366: 368-369Google Scholar, 10Hirschel B. Effect of rimonabant on weight reduction and cardiovascular risk.Lancet. 2005; 366: 369-370Abstract Full Text Full Text PDF PubMed Google Scholar Clearly, the search for the ideal antiobesity agent is not at an end.At the other end of the appetite regulation spectrum, there is a pressing need for more effective, better-tolerated appetite-stimulatory treatments. Loss of appetite and weight are major causes of morbidity and mortality in patients, including those with cancer, kidney failure, human immunodificiency virus, cardiac failure, inflammatory conditions, and postoperatively. Weight loss has an important impact on health economics. Undernutrition is estimated to increase the duration of 10% of hospital admissions by an average of 5 days, costing approximately £266 million annually in the United Kingdom.11Kings Fund A positive approach to nutrition as a treatment.Report of a working party charied by JE Lennard-Jones. 2003Google Scholar Although a comprehensive overview of anorexia and cachexia is beyond the scope of this review, which will focus mainly on obesity, the potential role of gut hormones in this area will be briefly discussed.Long-Term and Short-Term Energy Balance SignalsPeripheral signals involved in regulation of body weight and ingestive behavior are often categorized as long-acting adiposity signals, such as insulin leptin and other adipokines and short-acting gastrointestinal factors. Long-acting signals characteristically reflect the levels of energy stores and regulate body weight and the amount of energy stored as fat over the long term. Short-acting gastrointestinal signals are typified by gut hormones such as CCK and mechanical factors, such as gastric distension, which characteristically relay a sense of “fullness” resulting in postprandial satiation and meal termination. More recently identified appetite regulating hormones from the gut, including the appetite inhibiting hormone peptide YY (PYY) and the appetite-stimulating hormone ghrelin, appear to blur the boundaries between long- and short-term appetite signals, with evidence emerging that they are involved in both regulation of appetite on a meal-by-meal basis and also in longer term energy balance. In addition, the incretin glucagon-like peptide 1 (GLP-1), has been shown to inhibit appetite. This is reviewed in detail elsewhere in this issue and will not be covered here in depth. This review will focus on the evidence for a role of the gut hormones ghrelin, PYY, oxyntomodulin, and pancreatic polypeptide (PP) in the short- and long-term regulation of energy balance.Central Integration of Peripheral SignalsClearly, peripheral hunger and satiety signals require central integration to allow efficient energy homeostasis. Neurohormonal signals from the gut and adipose tissue converge on the hypothalamus where they are integrated, and in turn regulate energy intake and energy expenditure. The reader is referred to a number of excellent reviews of the hypothalamic neurocircuits regulating energy balance.12Cone R.D. Cowley M.A. Butler A.A. Fan W. Marks D.L. Low M.J. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis.Int J Obes Relat Metab Disord. 2001; 25: S63-S67Crossref PubMed Google Scholar, 13Schwartz M.W. Woods S.C. Porte Jr, D. Seeley R.J. Baskin D.G. Central nervous system control of food intake.Nature. 2000; 404: 661-671Crossref PubMed Google Scholar, 14Kalra S.P. Dube M.G. Pu S. Xu B. Horvath T.L. Kalra P.S. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight.Endocr Rev. 1999; 20: 68-100Crossref PubMed Scopus (1111) Google Scholar, 15Flier J.S. Obesity wars: molecular progress confronts an expanding epidemic.Cell. 2004; 116: 337-350Abstract Full Text Full Text PDF PubMed Scopus (624) Google Scholar In brief, a vital component of the hypothalamic regulatory circuits is the arcuate nucleus. Two key neuronal populations have been identified within the arcuate nucleus with opposing effects on energy balance. A group of neurons in the medial arcuate nucleus coexpress neuropeptide Y (NPY) and agouti-related peptide (AgRP) and act to stimulate food intake and weight gain. In contrast, pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript coexpressing neurons in the lateral arcuate nucleus inhibit feeding and promote weight loss. The balance between activity of these neuronal circuits is critical to body weight regulation.Satiety is also regulated by the hindbrain. The nucleus of the solitary tract (NTS) and the area postrema, components of the dorsal vagal complex, receive inputs from vagal afferents and circulating factors, and are reciprocally connected with hypothalamic nuclei controlling energy balance. These brainstem centers can also respond independently to peripheral signals when communication with higher brain centers are surgically interrupted.16Grill H.J. Smith G.P. Cholecystokinin decreases sucrose intake in chronic decerebrate rats.Am J Physiol. 1988; 254: R853-R856PubMed Google Scholar In addition, cortical inputs in terms of emotional, social, and learned behavior, as well as inputs from reward circuits, including the mesolimbic dopaminergic system, all impact upon energy balance and communicate with the hypothalamus.Peripheral feedback to the hypothalamus is complex, as illustrated in Figure 1. Many circulating signals, including gut hormones, have direct access to the arcuate nucleus. Leptin is the archetypal peripheral signal acting directly on the arcuate nucleus.15Flier J.S. Obesity wars: molecular progress confronts an expanding epidemic.Cell. 2004; 116: 337-350Abstract Full Text Full Text PDF PubMed Scopus (624) Google Scholar, 17Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Positional cloning of the mouse obese gene and its human homologue.Nature. 1994; 372: 425-432Crossref PubMed Scopus (7967) Google Scholar In contrast, other peripheral signals influence the hypothalamus indirectly via afferent neuronal pathways and brainstem circuits. The most extensively characterized of these is CCK, which binds to receptors on the vagus nerve, thus activating the NTS, which in turn, relays information to the hypothalamus. Similarly, GLP-1R expressing neurons of the NTS project to hypothalamic regions involved in appetite control, including the arcuate, dorsomedial, and paraventricular nuclei. In the cases of ghrelin and PYY, there is evidence for both a direct action on the arcuate nucleus and an action via the vagus nerve and brainstem.Figure 1Overview of peripheral factors regulating energy balance and their routes of signaling to the brain.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Ghrelin, the Hunger HormoneGhrelin is the only known circulating orexigen. In contrast, all the other peripheral factors that regulate energy balance act to restrain eating and weight gain. Ghrelin was discovered as an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R1a).18Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Crossref PubMed Scopus (4313) Google Scholar However, early work on this peptide demonstrated a growth hormone-independent action to powerfully increase food intake and body weight. The predominant focus of subsequent research has shifted onto the role of ghrelin in energy balance.19Tschop M. Smiley D.L. Heiman M.L. Ghrelin induces adiposity in rodents.Nature. 2000; 407: 908-913Crossref PubMed Scopus (2219) Google Scholar, 20Wren A.M. Small C.J. Ward H.L. Murphy K.G. Dakin C.L. Taheri S. Kennedy A.R. Roberts G.H. Morgan D.G. Ghatei M.A. Bloom S.R. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.Endocrinology. 2000; 141: 4325-4328Crossref PubMed Google Scholar, 21Nakazato M. Murakami N. Date Y. Kojima M. Matsuo H. Kangawa K. Matsukura S. A role for ghrelin in the central regulation of feeding.Nature. 2001; 409: 194-198Crossref PubMed Scopus (1864) Google Scholar, 22Wren A.M. Small C.J. Abbott C.R. Dhillo W.S. Seal I. Cohen M.A. Batterham R.L. Taheri S. Stanley S.A. Ghatei M.A. Bloom S.R. Ghrelin causes hyperphagia and obesity in rats.Diabetes. 2001; 50: 2540-2547Crossref PubMed Google ScholarGhrelin is a 28-amino acid peptide, cleaved from a precursor, preproghrelin.18Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Crossref PubMed Scopus (4313) Google Scholar It is principally synthesized in endocrine cells of the stomach, termed X/A-like or ghrelin cells, and particularly found in the gastric fundus.18Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Crossref PubMed Scopus (4313) Google Scholar, 23Date Y. Kojima M. Hosoda H. Sawaguchi A. Mondal M.S. Suganuma T. Matsukura S. Kangawa K. Nakazato M. 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Nakao K. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans.J Clin Endocrinol Metab. 2001; 86: 4753-4758Crossref PubMed Scopus (772) Google Scholar Ghrelin undergoes posttranslational modification with covalent attachment of a medium-chain fatty acid, typically octanoic acid, to the serine-3 residue. This acylation is entirely unique among biologically active peptides and is required for ghrelin to bind to and activate its classical receptor, the GHS-R1a.18Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Crossref PubMed Scopus (4313) Google Scholar The GHS-R1a is widely expressed. In the CNS, it is found in areas involved in regulation of appetite and energy balance including hypothalamic nuclei, the dorsal vagal complex, and the mesolimbic dopaminergic system.25Guan X.M. Yu H. Palyha O.C. McKee K.K. Feighner S.D. Sirinathsinghji D.J. Smith R.G. van der Ploeg L.H. Howard A.D. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues.Brain Res Mol Brain Res. 1997; 48: 23-29Crossref PubMed Scopus (626) Google Scholar, 26Gnanapavan S. Kola B. Bustin S.A. Morris D.G. McGee P. Fairclough P. Bhattacharya S. Carpenter R. Grossman A.B. Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.J Clin Endocrinol Metab. 2002; 87: 2988Crossref PubMed Scopus (762) Google Scholar, 27Zigman J.M. Jones J.E. Lee C.E. Saper C.B. Elmquist J.K. Expression of ghrelin receptor mRNA in the rat and the mouse brain.J Comp Neurol. 2006; 494: 528-548Crossref PubMed Scopus (282) Google Scholar Peripherally, it is expressed in the pituitary, and pharmacologically ghrelin acts at both pituitary and hypothalamic levels to powerfully stimulate growth hormone secretion.18Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.Nature. 1999; 402: 656-660Crossref PubMed Scopus (4313) Google Scholar, 20Wren A.M. Small C.J. Ward H.L. Murphy K.G. Dakin C.L. Taheri S. Kennedy A.R. Roberts G.H. Morgan D.G. Ghatei M.A. Bloom S.R. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.Endocrinology. 2000; 141: 4325-4328Crossref PubMed Google Scholar, 28Date Y. Murakami N. Kojima M. Kuroiwa T. Matsukura S. Kangawa K. Nakazato M. Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats.Biochem Biophys Res Commun. 2000; 275: 477-480Crossref PubMed Scopus (250) Google Scholar, 29Takaya K. Ariyasu H. Kanamoto N. Iwakura H. Yoshimoto A. Harada M. Mori K. Komatsu Y. Usui T. Shimatsu A. Ogawa Y. Hosoda K. Akamizu T. Kojima M. Kangawa K. Nakao K. Ghrelin strongly stimulates growth hormone release in humans.J Clin Endocrinol Metab. 2000; 85: 4908-4911Crossref PubMed Scopus (599) Google Scholar, 30Wren A.M. Small C.J. Fribbens C.V. Neary N.M. Ward H.L. Seal L.J. Ghatei M.A. Bloom S.R. The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.Neuroendocrinology. 2002; 76: 316-324Crossref PubMed Scopus (124) Google Scholar The physiologic relevance of ghrelin in GH regulation is debated. Ghrelin is not essential for GH secretion, as ghrelin and GHS-R1a null mice are not growth restricted, but it may play a role in augmentation of GHRH-stimulated GH pulses.31Sun Y. Ahmed S. Smith R.G. Deletion of ghrelin impairs neither growth nor appetite.Mol Cell Biol. 2003; 23: 7973-7981Crossref PubMed Scopus (365) Google Scholar, 32Sun Y. Wang P. Zheng H. Smith R.G. 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Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin.Endocr Rev. 2004; 25: 426-457Crossref PubMed Scopus (668) Google Scholar The physiologic relevance of these actions remains unclear, and the major role of ghrelin is generally accepted to be in regulation of energy balance. There is also evidence for a number of pharmacologic actions of des-acyl ghrelin, which must be mediated via receptors other than the GHS-R1a.35Thompson N.M. Gill D.A. Davies R. Loveridge N. Houston P.A. Robinson I.C. Wells T. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor.Endocrinology. 2004; 145: 234-242Crossref PubMed Scopus (257) Google Scholar The physiologic significance of these actions is contentious, as reviewed elsewhere.33Van Der Lely A.J. Tschop M. Heiman M.L. Ghigo E. 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Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP).Endocrinology. 2004; 145: 2007-2012Google ScholarWhen administered into the CNS, ghrelin stimulates food intake as potently as NPY, previously the most powerful known orexigen, and more powerfully than any other substance examined.19Tschop M. Smiley D.L. Heiman M.L. Ghrelin induces adiposity in rodents.Nature. 2000; 407: 908-913Crossref PubMed Scopus (2219) Google Scholar, 20Wren A.M. Small C.J. Ward H.L. Murphy K.G. Dakin C.L. Taheri S. Kennedy A.R. Roberts G.H. Morgan D.G. Ghatei M.A. Bloom S.R. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion.Endocrinology. 2000; 141: 4325-4328Crossref PubMed Google Scholar, 21Nakazato M. Murakami N. Date Y. Kojima M. Matsuo H. Kangawa K. Matsukura S. A role for ghrelin in the central regulation of feeding.Nature. 2001; 409: 194-198Crossref PubMed Scopus (1864) Google Scholar Ghrelin also stimulates appetite and food intake when administered systemically in rodents19Tschop M. Smiley D.L. Heiman M.L. Ghrelin induces adiposity in rodents.Nature. 2000; 407: 908-913Crossref PubMed Scopus (2219) Google Scholar, 22Wren A.M. Small C.J. Abbott C.R. Dhillo W.S. Seal I. Cohen M.A. Batterham R.L. Taheri S. Stanley S.A. Ghatei M.A. Bloom S.R. Ghrelin causes hyperphagia and obesity in rats.Diabetes. 2001; 50: 2540-2547Crossref PubMed Google Scholar and humans.38Wren A.M. Seal L.J. Cohen M.A. Brynes A.E. Frost G.S. Murphy K.G. Dhillo W.S. Ghatei M.A. Bloom S.R. Ghrelin enhances appetite and increases food intake in humans.J Clin Endocrinol Metab. 2001; 86: 5992-5995Crossref PubMed Scopus (1330) Google Scholar This property is unique to ghrelin and not shared by any known neuropeptide or circulating hormone. The duration of feeding stimulation in response to central or peripheral ghrelin administration is short, similar to that observed for central NPY. Indeed, several lines of evidence suggest that ghrelin acts via arcuate NPY/AgRP neurons, almost all of which express the GHS-R1a.39Willesen M.G. Kristensen P. Romer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat.Neuroendocrinology. 1999; 70: 306-316Crossref PubMed Google Scholar Ghrelin stimulates feeding most potently when injected directly into the arcuate nucleus and also stimulates release of NPY from hypothalamic explants in vitro.22Wren A.M. Small C.J. Abbott C.R. Dhillo W.S. Seal I. Cohen M.A. Batterham R.L. Taheri S. Stanley S.A. Ghatei M.A. Bloom S.R. Ghrelin causes hyperphagia and obesity in rats.Diabetes. 2001; 50: 2540-2547Crossref PubMed Google Scholar, 30Wren A.M. Small C.J. Fribbens C.V. Neary N.M. Ward H.L. Seal L.J. Ghatei M.A. Bloom S.R. The hypothalamic mechanisms of the hypophysiotropic action of ghrelin.Neuroendocrinology. 2002; 76: 316-324Crossref PubMed Scopus (124) Google Scholar Arcuate NPY/AgRP neurons are activated by ghrelin, as demonstrated by enhanced c-fos, NPY, and AgRP expression following ghrelin administration and by electrophysiologic studies.21Nakazato M. Murakami N. Date Y. Kojima M. Matsuo H. Kangawa K. Matsukura S. A role for ghrelin in the central regulation of feeding.Nature. 2001; 409: 194-198Crossref PubMed Scopus (1864) Google Scholar, 40Dickson S.L. Luckman S.M. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6.Endocrinology. 1997; 138: 771-777Crossref PubMed Scopus (201) Google Scholar, 41Asakawa A. Inui A. Kaga T. Yuzuriha H. Nagata T. Fujimiya M. Katsuura G. Makino S. Fujino M.A. Kasuga M. 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