This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Ghrelin is a gut-derived acylated peptide hormone that stimulates secretion of growth hormone (GH) and ACTH, as well as orexigenesis. Our central thesis is that ghrelin protects mammals against starvation by: increasing appetite and food intake;increasing secretion of GH to protect lean body mass;decreasing locomotor activity to preserve calories;and regulating partitioning, including glucose homeostasis. The overall hypotheses of this protocol are: (1) cortisol and insulin are the dominant negative regulators of ghrelin release during normal daily patterns of feeding and short-term fasting;and (2) this specific control mechanism is altered by obesity, such that the lack of adequate ghrelin suppression contributes to overeating. Our laboratory has developed sensitive and specific sandwich assays for intact active acyl-ghrelin and des-acyl ghrelin. Using these assays, we will determine the temporal relationships between pulsatile acyl- and des-acyl ghrelin secretion and circulating concentrations of insulin, cortisol and GH in healthy lean (insulin sensitive) and obese (insulin resistant) adults. Subjects will have frequent blood sampling (every 10 min for 27 h) during fed and fasting (37.5 h) admissions. These results will provide the preliminary data for predicting the outcomes of direct interventions in other studies that will directly control ghrelin secretion. It will determine the effect of cortisol on ghrelin secretion to determine its role in diurnal variation in ghrelin secretion. We will determine whether insulin inhibits ghrelin secretion and whether glucose-related ghrelin suppression is mediated by insulin.
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