Body weight regulation involves adjustments in food intake that compensate for fluctuations in energy stores. These adjustments are comprised of alterations in meal number, size, or both. Compared with the well understood systems that regulate meal termination, and thus, meal size, those that regulate meal initiation and frequency remain enigmatic. The recently discovered enteric hormone, ghrelin, is implicated in the cascade of events leading to meal initiation, but evidence favoring this assertion is largely circumstantial. We propose to test critically the requirement for ghrelin and its most well established CNS target - NPY/Agrp neurons - in meal initiation, using loss-of-function experiments. We will address the following broad questions. (1) Is ghrelin signaling required for normal meal initiation, meal termination, or both? Using state-of-the art equipment to measure food intake continuously on a second-to-second basis, we will assess the effect on meal number, size, and duration, of novel, highly potent antagonists of the ghrelin receptor (GHS-R), at doses that decrease overall food intake. Experiments will be conducted on ad libitum-fed mice as well as those subjected to a variety of acute and chronic states of energy deficit that challenge meal-initiation signals. We will study wild-type and GHS-R /- mice in parallel, both to verify that the anorectic effects of GHS-R antagonists result specifically from blockade of the GHS-R, and also to compare the effects of complementary pharmacologic and genetic ablation of GHS-R signaling. (2) Are NPY/Agrp neurons required for normal meal initiation, energy homeostasis, and response to ghrelin? Our co-investigator, Dr. Greg Barsh, has created mice in which NPY/Agrp neurons are gradually and continuously destroyed in adulthood. The animals are a valuable resource to determine the requirement for NPY/Agrp neurons in each of ghrelin's known anabolic actions, as well as to assess the role of NPY/Agrp neurons themselves in meal patterning and overall energy homeostasis. We propose a thorough phenotyping analysis of these mice to address these issues. (3) Do intracellular signaling events triggered by ghrelin in key hypothalamic neurons - especially NPY/Agrp neurons - oppose those triggered by leptin and insulin (and vice versa)? Together, these studies have the potential to fundamentally advance our understanding of feeding biology at the molecular, cellular, and behavioral level.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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University of Washington
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O-Sullivan, InSug; Zhang, Wenwei; Wasserman, David H et al. (2015) FoxO1 integrates direct and indirect effects of insulin on hepatic glucose production and glucose utilization. Nat Commun 6:7079
Lee, Woo Je; Tateya, Sanshiro; Cheng, Andrew M et al. (2015) M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling. Diabetes 64:2836-46
Morton, Gregory J; Kaiyala, Karl J; Foster-Schubert, Karen E et al. (2014) Carbohydrate feeding dissociates the postprandial FGF19 response from circulating bile acid levels in humans. J Clin Endocrinol Metab 99:E241-5
Lu, Min; Sarruf, David A; Li, Pingping et al. (2013) Neuronal Sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J Biol Chem 288:10722-35
Schwartz, Michael W; Baskin, Denis G (2013) Leptin and the brain: then and now. J Clin Invest 123:2344-5
Guyenet, Stephan J; Nguyen, Hong T; Hwang, Bang H et al. (2013) High-fat diet feeding causes rapid, non-apoptotic cleavage of caspase-3 in astrocytes. Brain Res 1512:97-105
Thaler, Joshua P; Yi, Chun-Xia; Schur, Ellen A et al. (2012) Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122:153-62
Schwartz, Michael W (2012) An inconvenient truth about obesity. Mol Metab 1:2-4
Guyenet, Stephan J; Schwartz, Michael W (2012) Clinical review: Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 97:745-55
Lu, Min; Sarruf, David A; Talukdar, Saswata et al. (2011) Brain PPAR-? promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 17:618-22

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