Ghrelin is an orexigenic, glucoregulatory and antidepressant peptide hormone derived mainly from a distinct group of ghrelin cells dispersed throughout the gastric mucosa. Its plasma levels rise upon mild caloric restriction to stimulate food intake and fat storage and upon severe caloric restriction to prevent life-threatening falls i blood glucose. Ghrelin levels also rise following psychosocial stress, minimizing stress-induced depression and inducing food reward behavior. These key physiologic and behavioral effects of ghrelin action are emphasized by the hypoglycemic and depression phenotypes observed in mouse models of ghrelin, ghrelin receptor, and/or ghrelin O-acyltransferase deficiency upon exposure to prolonged caloric restriction or chronic psychosocial stress. Despite critical roles fo ghrelin in glucose homeostasis and the coordinated response to psychosocial stress, relatively little is known about the mechanisms regulating ghrelin secretion. The central theme of this proposal is to identify mechanisms mediating ghrelin secretion at the level of the ghrelin cell, with a focus on 1-adrenergic receptor (1-AR) signaling. The experiments have been designed to determine if 1-AR signaling within ghrelin cells is required for the ghrelin response to calorc restriction, if ghrelin cell 1-ARs are required for appropriate ghrelin secretory and mood responses to chronic psychosocial stress, and if the pentose phosphate pathway and ChREBP (carbohydrate response element-binding protein) mediate the effects of 1-ARs and glucose on ghrelin cell secretory responses, as hypothesized. The proposal will utilize a one-of-a-kind collection of techniques and tools developed to study and manipulate the ghrelin cell. This includes a system for primary culture of dispersed gastric mucosal cells with which to assess ghrelin secretion ex vivo, ghrelin-Cre transgenic mice which permit selective deletion of 1-ARs and functional ChREBP from ghrelin cells when crossed with novel conditional 1-AR and functional ChREBP knockout lines, and ghrelin- hrGFP transgenic mice that report on the location and allow for fluorescent-activated cell sorting of ghrelin cells. This unique collection f mouse lines and techniques and the accompanying in vivo metabolic and behavioral studies, ex vivo secretion experiments, and other assessments will allow our proposed hypotheses regarding ghrelin secretion and the ghrelin response to different extremes of caloric restriction, food intake and psychosocial stress to be rigorously tested. Ultimately, it is hoped that the planned studies advance our understanding of the coordinated physiologic and behavioral responses to caloric restriction and chronic psychosocial stress so that new treatment modalities for extremes of body weight, chronic stress, depression, and eating disorders such as anorexia nervosa may be uncovered.
The peptide hormone ghrelin is recognized as having important effects on maintaining blood glucose levels, defending body weight, mediating hedonic eating, and limiting depression, especially in the settings of severe caloric restriction, cachexia and chronic psychosocial stress. The experiments proposed in this grant application have been designed to determine key molecular mechanisms regulating ghrelin secretion at the level of the ghrelin cell, with a focus on the role of ghrelin cell expression of 1-adrenergic receptors and their interactions with the pentose phosphate pathway and ChREBP (carbohydrate response element-binding protein). These mechanistic studies will provide fundamental insights into ghrelin cell physiology and ghrelin action and should advance our understanding of the coordinated physiologic and behavioral responses to caloric restriction and chronic psychosocial stress.
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