The burden placed on the healthcare economy in the United States by obesity and obesity-related disorders has been estimated at $100 billion annually. Obesity represents a complex disorder that is often linked to metabolic disorders, such as diabetes mellitus and nonalcoholic fatty liver disease, and occurs as a result of interactions among genetic, environmental, and nutritional factors. The gastrointestinal (GI) tract represents the sole portal for the entry, processing, and absorption of nutrients, a process that is regulated largely by mucosal peptides released postprandially. As such, GI peptides represent ideal therapeutic targets for a variety of nutritional disorders, including obesity and diabetes. We have previously identified glucose-dependent insulinotropic polypeptide (GIP) as the primary hormonal mediator of the enteroinsular axis. GIP is released by a subset of intestinal mucosal cells in response to oral glucose and fat, thereby stimulating the release of insulin from pancreatic beta-islet cells (i.e., the enteroinsular axis). This process can be disrupted by the use of a GIP-specific antagonist (ANTGIP) developed in our laboratory and the sole intellectual property of EnteroMed. Beyond its role as an effector of the enteroinsular axis, we have reported that ANTGIP inhibits glucose absorption from the isolated rat intestine. We have also identified GIP receptors on human adipocytes, where GIP inhibits isoproterenol-induced lipolysis. A recent study has corroborated our findings that GIP plays a key role in the pathogenesis of obesity. Miyawaki et al. (Nat Med 2002; 2002; 8:738-742) reported that, in contrast to normal mice, GIP receptor-deficient mice did not develop obesity when fed a high-fat diet. We hypothesize that ANTGIP will likewise prevent obesity by two mechanisms: (1) by preventing postprandial hyperinsulinemia and its secondary anabolic state, a strategy that forms the basis of highly successful carbohydrate restrictive diets; and (2) by preventing lipogenesis via a direct inhibitory effect on fat cells. The specific aim of this proposal is to determine whether ANTGIP can prevent obesity in mice. We will study, over a 6 month period, the effect of b.i.d. ANTGIP in both normal mice fed a high fat diet and mice genetically predisposed to the development of obesity. The primary endpoints will be mouse weight and postprandial serum glucose/insulin levels. The studies outlined in this proposal will enable us to determine whether a GIP-specific receptor antagonist may ultimately be useful in the prevention of lipid deposition and in preventing hyperinsulinemia, lipogenesis, and obesity in humans.