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Gut Hormones and Metabolism

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Gut Hormones and Metabolism Gut Hormones and Metabolism Rebecca Scott* & Steve Bloom** *Department of Investigative Medicine, **Head of Division of Diabetes, Endocrinology and Metabolism, Commonwealth Building, Hammersmith Hospital, Imperial College London, Du Cane Road, London, W12 0NN www.tocris.com The gut is the largest endocrine organ in the body. More than 30 hormones are produced by the gastrointestinal tract, pancreas and fat, with many other related peptides produced in the brain. Many gut hormones are Products available from Tocris released by the direct action of ingested nutrients on enteroendocrine cells found within the intestine. These hormones act to control food intake and energy expenditure. AMPK A 769662, AICAR, Dorsomorphin, Metformin, PF 06409577, Gut-Brain Axis ARC SAMS Peptide Insulin Bombesin Receptors The hypothalamus is the co-ordination center for energy homeostasis, and the arcuate receptor Insulin receptor NPY receptor Melanocortin NPY receptor Bombesin, GRP (human), GRP (porcine), nucleus (ARC) in the hypothalamus is the epicenter for integration of signals about the receptor Neuromedin B (porcine), PD 176252 energy status and requirements of an individual. The ARC contains two distinct populations GLP-1 Calcitonin and Related Receptors receptor BIBN 4096, CGRP 8-37 (human), of neurons. NPY and AgRP neurons are orexigenic (stimulate appetite), and are activated by Arcuate nucleus (ARC) NPY/AgRP POMC/CART CGRP 8-37 (rat), α-CGRP (human) signals such as ghrelin, while CART and POMC neurons are anorexigenic (reduce appetite), Cannabinoid Receptor AM 251, AM 281, AM 630, HU 308, and are stimulated by GLP-1 and PYY. These neurons reciprocally innervate each other, so JWH 133, SR 141716A Leptin receptor Ghrelin receptor Melanocortin Leptin receptor Cholecystokinin1 Receptor activation of the CART/POMC neurons turns off the NPY/AGRP neurons and vice versa. receptor A-71623, CCK Octapeptide, sulfated, The ARC receives inputs from many different sources. It lies close to the median eminence, CI 988, Devazepide, Gastrin I (human), YM 022 which lacks a blood brain barrier, allowing direct access to hormones from the periphery. Galanin Receptors Increases food uptake Decreases food uptake The vagus nerve connects the gastrointestinal tract to the hypothalamus, relaying messages Galanin (1-29) (rat, mouse), “Orexigenic” “Anorexigenic” Galanin (1-30) (human), M 1145, about gut hormones and gastrointestinal distension. Reciprocal connections also exist M40, M617, M871 between the brain stem and the hypothalamus. The ARC then relays messages to other Ghrelin Receptors Orexigenic Mediators [D-Lys3]-GHRP-6, Ghrelin (human), hypothalamic nuclei, such as the ventromedial nucleus, the dorsomedial nucleus and the Ghrelin (rat), Tabimorelin, YIL 781 HORMONE RELEASE FROM RECEPTOR Glucagon Receptor lateral hypothalamic area. There is subsequent output to the sympathetic nervous system, Agouti-related peptide (AgRP) Hypothalamus, particularly Inverse agonist of Melanocortin des-His1-[Glu9]-Glucagon (1-29) amide, arcuate nucleus MC3 and MC4 receptors the thyroid axis, the limbic system, and back to the vagus, which then control food L-168,049, Oxyntomodulin Endocannabinoids Central nervous system CB1 and CB2 receptors Sympathetic nerves Glucagon-Like Peptide Receptors intake and energy expenditure. Galanin Enteric neurons, central and G-protein coupled receptors peripheral nervous system GAL1, GAL2 and GAL3 Exendin-3 (9-39) amide, Exendin-4, Glucagon-like peptide 1 (1-37) Ghrelin X/A-like cells of the stomach Ghrelin receptor (also increases (human, rat), Glucagon-like peptide 1 preference for sweet food) (7-36) amide (human, rat) Gut Hormones and Obesity Growth hormone-releasing Hypothalamus Growth hormone releasing hormone (GHRH) hormone receptor Insulin and Insulin-like Receptors In normal circumstances, Melanin-concentrating hormone Hypothalamus Melanin-concentrating 6bK, BMS 536924, Insulin (human) Hormone Obesity Weight loss (MCH) hormone receptor recombinant, Mitoglitazone, co-ordination of the gut-brain axis NBI 31772, Picropodophyllotoxin PYY â post-prandial rise â Neuropeptide Y (NPY) Hypothalamus and enteric Y1, Y2 and Y5 receptors ensures that an individual maintains neurons (increases food intake via Y Leptin Receptors PP â/á â/á 1 their weight within a narrow range. and Y5; decreases food intake LEP (116-130) (mouse) via Y receptor) However, persistent excessive food GLP-1 â post-prandial rise â 2 Melanocortin Receptors Orexin B Intestine and hypothalamus OX and OX receptors consumption can overcome the CCK â/á â 1 2 ACTH (1-39), Melanotan II, ML 00253764, SHU 9119 normal homeostatic mechanisms Leptin Increased baseline levels â and lead to the development of but increased resistance Anorexigenic Mediators Motilin Receptors obesity. Furthermore, once a person to action ANQ 11125, Motilin (human, porcine) HORMONE RELEASE FROM RECEPTOR mTOR has become obese, their physiology Ghrelin Reduced baseline levels á Amylin β-cells of the pancreas AMY1a, AMY2a and AMY3a AZD 3147, eCF 309, PP 242, changes to make weight loss even and failure to suppress (Calcitonin receptor core, with Rapamycin, Torin 1, Torin 2 an associated receptor activity harder. In obese patients, there is a post-prandially Neuromedin U Receptors relative reduction in levels and modifying protein RAMP1, Amylin á â RAMP2 or RAMP3) Neuromedin S (rat), Neuromedin U (rat) efficacy of the satiety hormones PYY, Calcitonin gene-related peptide Enteric neurons, central and CGRP receptor (Calcitonin NPY Receptors PP, GLP-1 and CCK. There is also a resistance to the effects of leptin, and an increased Leptin (CGRP) peripheral nervous system receptor-like receptor with [Leu31,Pro34]-Neuropeptide Y sensitivity to ghrelin. These changes stop people feeling full and increase food consumption. associated RAMP1) (human, rat), BIBO 3304, BIIE 0246, Adipose tissue Cholecystokinin (CCK) I-cells duodenum CCK1 and CCK2 receptors GW 438014A, Neuropeptide Y Unfortunately, when people diet, the body tries to defend against weight loss. The satiety Cocaine and amphetamine- Hypothalamus The CART receptor has not (human, rat), Peptide YY (3-36) hormones (such as PYY, CCK, leptin and amylin) fall, while the orexigenic NPY and ghrelin regulated transcript (CART) been fully identified Opioid Receptors increase. Metabolic rate also slows. This makes it progressively harder to lose weight and Liver Corticotrophin-releasing Hypothalamus CRHR1 and CRHR2 receptors (±)-U-50488, DAMGO, Naltrindole, hormone (CRH) (reduces or increases food maintain weight loss. nor-Binaltorphimine, SNC 80, intake depending on route of β-Funaltrexamine administration) Orexin Receptor Gastrin releasing peptide Enteric neurons and central BB2 receptor Ghrelin 11 15 nervous system [Ala ,D-Leu ]-Orexin B, EMPA, Gut Hormones Drug Therapies and Bariatric Surgery Orexin A (human, rat, mouse), Orexin B Stomach Glucagon α-cells of the pancreas Glucagon receptor (human), SB 334867, TCS OX2 29 Glucagon-like peptide 1 L-cells of the ileum GLP-1 receptor (also reduces Gut hormones can be used as a pharmacological therapy for obesity. Naturally-occurring Insulin, PP Secretin Receptors gut hormones have very short half-lives in the body, which limit their use. However, preference for sweet food) Pancreas Glucagon-like peptide 2 L-cells of the ileum GLP-2 receptor Secretin (human), Secretin (rat) long-lasting versions are being developed. Exendin-4 is a GLP-1 analog first discovered in Glucose-dependent K-cells of the jejunum GIP receptors Somatostatin Receptors the saliva of the Gila monster. It is resistant to the enzyme dipeptidyl peptidase IV, which insulinotropic peptide Cyclosomatostatin, CYN 154806, breaks down GLP-1, and therefore has a prolonged half-life. The synthetic version, Insulin β-cells of the pancreas Insulin receptor L-803,087, Octreotide, Seglitide, Somatostatin exenatide, is a common treatment for diabetes. Another long-acting GLP-1 analog, Leptin Adipose tissue Leptin receptor VIP Receptors liraglutide, is available as a treatment for both diabetes and obesity. Stabilized analogs α-melanocortin-stimulating Hypothalamus Melanocortin MC3 and MC4 hormone (α-MSH) receptors [D-p-Cl-Phe6,Leu17]-VIP, Bay 55-9837, of both PYY and PP have been developed and have entered clinical trials as treatments VIP (human, rat, mouse, rabbit, for obesity. There is increasing evidence for targeting obesity with combinations of gut Neuromedin B Hypothalamus and enteric BB1 receptor Small intestine neurons canine, porcine) hormones. Chronic injections of oxyntomodulin, which activates both GLP-1 and glucagon Neuromedin U (NMU) Central nervous system and NMU1 and NMU2 receptors receptors, reduce body weight in obese patients, and a number of oxyntomodulin analogs intestine are in development as a treatment for obesity. Additionally, several drugs targeting both Neurotensin Central nervous system and NTS1 and NTS receptors the GLP-1 and GIP pathways, and triple-agonists at the GLP-1, GIP and glucagon N cells of intestine receptors, are being developed. Opioid Peptides (met-enkephalin, Enteric neurons µ, κ and δ-opioid receptors CKK leu-enkephalin, β-endorphin PYY and dynorphin) Bariatric surgery is now recognized as the most effective, lasting treatment for obesity. 3–36 References: Oxyntomodulin L-cells of the ileum Co-agonist of glucagon and Lean and Malkova (2016) Int. Journal of Surgery has two effects. Firstly, the size of the GI tract, particularly the stomach, is made GLP-1 receptors Obesity (London) 40 622 Meek (2016) 77 28 smaller, so patients
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