Ghrelin is a peptide hormone secreted mainly from cells of the gastrointestinal tract. It plays key roles in regulating food intake, energy homeostass and blood glucose. Circulating ghrelin rises during times of relative energy insufficiency, for example prior to set meals or upon more prolonged caloric restriction (CR), thus stimulating food intake and replenishment of energy stores. Low glucose levels also stimulate ghrelin release, initiating changes in insulin sensitivity and the secretion of insulin, glucagon and growt hormone, thus restoring normal blood glucose levels. The compensatory rise in ghrelin has been postulated to contribute to the rebound weight gain that often occurs in the setting of weight loss as achieved by dietary CR, and is required to prevent marked hypoglycemia when the CR is severe. Roux-en-Y gastric bypass (RYGB) represents a much more effective means of weight loss than CR, resulting in both a greater and more prolonged reduction of body weight, lowered mortality and amelioration of several comorbidities, including a rapid improvement in blood glucose levels of obese diabetic individuals. In contrast to most other forms of weight loss, including CR, most studies have shown an atypical ghrelin response (either decrease or lack of increase) following RYGB. Thus the differential ghrelin secretory response in the settings of CR (compensatory) vs. RYGB (atypical) may contribute to the differential efficacies of these two weight loss methods. However, the mechanisms controlling ghrelin secretion in general, including in the specific situations of chronic CR and RYGB, remain undetermined. The central theme of this proposal is to identify mechanisms mediating the differential ghrelin secretory responses to severe CR and RYGB. In this application, we will compare changes observed in calorically restricted vs. ad libitum-fed mice (Specific Aim 1) and in RYGB- manipulated vs. sham surgery-treated mice (Specific Aim 2). We will assess changes to the number of and ultra-structural organization of secretory granules within ghrelin cells and their distribution in relatin to other enter endocrine cells. We will assess changes in the sensitivity of ghrelin cells to sympathetic signaling and glucose. The findings from this proposal should provide important insights regarding the enteroendocrine contribution to both surgical and non-surgical weight loss. Our long-term objective is to uncover novel approaches to augment surgical weight loss or even to replace operative treatment for obesity and other metabolic diseases. Moreover, this research plan and its accompanying training plan will provide me with the opportunity to acquire research and analytical skills necessary to develop my own specific research interests and to pursue a career as a productive, independently-funded investigator in endocrinology and metabolism.