The Gut and Regulation of Body Weight

0021-972X/04/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 89(6):2576 –2582 Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0189 The Gut and Regulation of Body Weight KATIE WYNNE, SARAH STANLEY, AND STEVE BLOOM Endocrine Unit, Imperial College Faculty of Medicine, Hammersmith Hospital, London W12 ONN, United Kingdom Signals generated by the gastrointestinal tract are able to regulate appetite and influence body weight. Ghrelin is an orexigenic peptide produced by the stomach. Satiety signals derived from the intestine and pancreas include peptide YY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomodu- T HE OBESITY EPIDEMIC continues unabated, bringing with it the burden of serious complications such as diabetes, coronary heart disease, and cancer. The World Health Organization has described obesity as the greatest threat to human health, and therefore it has never been so important to understand the control of appetite. Over the last 10 yr, because of the discovery of leptin, many advances have been made in our understanding of the peripheral signals regulating appetite and energy homeostasis. Several peptides synthesized and secreted by the gastrointestinal tract are known to regulate food intake. Whereas social and learned behaviors significantly impact on meal patterns, peripheral factors play important roles in determining energy balance by controlling hunger and satiety. Hunger Ghrelin is the first identified peripherally active orexigenic factor. It is a 28-amino acid peptide with an acyl side chain, n-octanoic acid, which has been found to be essential for its actions on appetite. Ghrelin is the endogenous agonist of the GH secretagogue receptor (GHS-R) (1). The oxyntic cells of the stomach are the main site of ghrelin production. About two thirds of circulating ghrelin is thought to be produced by the stomach. However, ghrelinproducing cells have also been found in the duodenum, ileum, caecum, and colon. Both circulating and nutritional factors from within the gut lumen may trigger these cells to release ghrelin. It is, however, thought to be calorie intake, which is the primary regulator of plasma ghrelin levels (2). Circulating ghrelin concentrations have been shown to rise during a period of fasting, peak (to double the baseline concentration) just before eating, and fall rapidly after a meal, suggesting a role as a meal initiator (3). However, recent Abbreviations: AgRP, Agouti-related peptide; AP, area postrema; BBB, blood-brain barrier; CCK, cholecystokinin; CNS, central nervous system; DPPIV, dipeptidyl peptidase IV; GHS-R, GH secretagogue receptor; GLP-1, glucagon-like peptide 1; GLP-1R, GLP-1 receptor; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; OXM, oxyntomodulin; POMC, proopiomelanocortin; PP, pancreatic polypeptide; PYY, peptide YY. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. lin, and cholecystokinin. Signals from the gut and adipose tissue are integrated in the central nervous system to provide energy homeostasis. Knowledge of the body’s control of appetite is important because we strive to combat obesity in man. (J Clin Endocrinol Metab 89: 2576 –2582, 2004) work has failed show a relationship between plasma ghrelin concentrations and meal initiation (4). Furthermore, plasma ghrelin peaks can be conditioned by altering feeding schedule, suggesting a possible role in physiological preparation for a meal, rather than initiation of feeding (5). Plasma ghrelin concentrations also show a diurnal variation, in phase with leptin, with highest levels in the morning and lowest at night (3). GHS-Rs are widely expressed. In the central nervous system (CNS), they are found in the pituitary and hypothalamus, whereas peripheral receptor expression has been described in the myocardium, stomach, small intestine, pancreas, colon, adipose tissue, liver, kidney, placenta, and T cells. In addition, there is some evidence of additional receptor subtype(s) that bind the nonoctanoylated form of ghrelin. Ghrelin has been demonstrated to be a short-term regulator of food intake in both animals and man. Both central and peripheral ghrelin administrations increase calorie intake in animals (6). Furthermore, infusing antighrelin antibodies into the rat brain inhibits fasting-induced feeding, supporting ghrelin’s role as an endogenous regulator of food intake (7). Ghrelin is also effective in man, producing a 28% increase in food intake, when given iv to normal weight volunteers (8). Ghrelin may also be a regulator of long-term energy balance. Plasma ghrelin levels are strongly correlated with body weight. There is a reversible suppression of ghrelin associated with obesity, such that ghrelin levels normalize after diet-induced weight loss (9). The fall in plasma ghrelin concentration after bariatric surgery for obesity is thought to be partly responsible for the suppression of appetite and weight loss seen after these operations (9). Seven-day administration of ghrelin to rodents stimulates weight gain and adiposity secondary to increased food intake (2, 6). This fat deposition is promoted by a change in metabolism from fatty acid oxidation to glycolysis (2). However, ghrelin null animals do not have significantly altered body weight or food intake when compared with wild-type littermates (10). In addition to its actions on food intake, ghrelin induces a dose-dependent stimulation of GH release from the pituitary via its actions on the GHS-R in the hypothalamus (1, 2). However, it is important to note that the effects of ghrelin on 2576 Wynne et al. • Gut and Regulation of Body Weight food intake are independent of its effects on GH. Whereas ghrelin is known to increase adiposity, GH reduces adiposity. The effect of chronic ghrelin administration on food intake and body weight is still effective in dwarf GH-deficient rats (2). Ghrelin may be the first of a number of orexigenic factors that have physiological activity in man. However, as yet, no other circulating hormone derived from the gastrointestinal tract has been shown to stimulate food intake. Satiety After a meal, nutrients pass into the stomach and intestine, and a number of gastrointestinal signals are released. These peptides and other signals act to optimize the digestive process, and some also function as satiety signals. Peptide YY (PYY) and pancreatic polypeptide (PP) PYY, PP, and neuropeptide Y (NPY) all belong to a peptide family known as the PP-fold peptides. Their common tertiary structure, consisting of an ␣-helix and polyproline helix connected by a ␤-turn, results in a characteristic U-shaped peptide known as a PP-fold. In addition to a shared tertiary structure, there is significant homology between peptide sequences within the family. They all have 36 amino acids and contain several tyrosine residues. Furthermore (...truncated)