Obesity is a global public health problem. An increased understanding of the basic physiology and neurobiology of body weight homeostasis is critical in the prevention and treatment of obesity and related co-morbidities such as diabetes mellitus and coronary artery disease. Over the last decade, several critical metabolic signals and candidate central neuronal pathways that mediate their effects have been identified. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHSR, ghrelin receptor) has emerged as one of these potentially key metabolic signals. Ghrelin is a hormone that stimulates food intake, promotes the accumulation of body fat, and decreases energy expenditure. Previous work has also indicated that ghrelin signaling is required for development of the full phenotype of diet-induced obesity. Ghrelin also affects blood glucose levels, the release of insulin and possibly the sensitivity to insulin. The primary purpose of this current proposal is to gain a better understanding of ghrelin's role in the regulation of body weight homeostasis. The proposed experiments include neuroanatomical approaches to determine the projections of ghrelin-responsive neurons. In addition, a novel mouse model will be used to investigate the role of ghrelin receptor expression in two specific central nervous system sites -- the arcuate nucleus and the dorsal vagal complex -- in ghrelin's effects on food intake, the development of diet-induced obesity, glucose homeostasis, and locomotor activity. The proposed research will be performed under the mentorship of an internationally recognized expert in functional neuroanatomy, and is part of a training and career development plan designed to facilitate the applicant's transition to successful independent clinical scientist. Other elements of the development plan will include laboratory technique training, data presentations and various laboratory, mentor and scientific meetings. The proposed research will take place in the Division of Endocrinology, Diabetes and Metabolism at Beth Israel Deaconess Medical Center, where all the resources (equipment, technical expertise) to carry out the proposed research are readily available.
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