? Obesity is a major health concern in the United States, affecting 35% of the adult population and almost one fourth of children. Obesity causes or complicates a number of diseases, including cardiovascular disorders, diabetes and osteoarthritis. Obesity increases the risk of many forms of cancer. Obesity complicates the treatment of surgical patients and is a major risk factor for postoperative complications. At the physiologic level, obesity is a disorder of energy imbalance, developing when energy intake exceeds energy expenditure. Food intake is largely regulated by the central nervous system, particularly the hypothalamus. Through a combination of genetic and biochemical approaches, novel peptide mediators which regulate energy homeostasis have recently been identified, and are the focus of major investigative efforts. While it seems intuitive that peptides that regulate food intake would also affect secretion of digestive enzymes, few studies have addressed this topic. The overall hypothesis of this proposal is that feeding peptides regulate pancreatic exocrine secretion via neural control mechanisms. This hypothesis is encompassed in the following specific aims: (1 To investigate the mechanisms by which ghrelin and CART peptide regulate pancreatic exocrine secretion in vivo: (2 To define the cellular mechanisms that regulate expression and release of neuronal ghrelin and CART peptide; (3 To determine the cellular mechanisms by which ghrelin and CART peptide regulate excitability of parasympathetic neurons that project to the pancreas; and (4 To study long-term cellular mechanisms by which feeding neuroligands regulate pancreatic neurons. ? ?
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