Neuroendocrinology of energy balance control: role of glucagon-like-peptide-1

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DESCRIPTION (provided by applicant): Project summary: candidate, environment, and research. This proposal describes a 5-year training program designed to provide the candidate with the expertise needed to achieve his long-term goal of developing a career as an independent behavioral neuroscientist at an academic research university. The candidate received a Ph.D. in 2006 and has since been conducting research as a postdoctoral fellow in the Department of Psychology and the Neuroscience Graduate Groups at the University of Pennsylvania. Both the Psychology and Neuroscience Graduate Groups have well-established research programs and a strong research tradition that together with other interdisciplinary institutes at the University of Pennsylvania will provide an ideal training environment for the candidate. The proposed primary mentor, Dr. Harvey J. Grill is a well-established researcher in the field of behavioral neuroscience and an expert in the neural circuits and neurochemical systems that control food intake and energy expenditure. Given the novel interdisciplinary approaches of the proposed research the candidate will also be guided by a co-mentor, Dr. Kendra K. Bence, a prominent junior molecular biologist in the fields of diabetes and obesity research. The research plan focuses on the neuropeptide glucagon-like-peptide-1 (GLP-1) and its role in controlling for food intake, body weight regulation and glucose homeostasis. The experiments described here take advantage of novel in vivo and in vitro approaches to determine: [1] the necessity of GLP-1 receptors on vagal afferent fibers to glycemic and energy balance regulation; [2] the food intake inhibition and glycemic responses to exogenous and endogenous activation of hindbrain GLP-1 receptor-expressing neurons in the nucleus tractus solitarius of the dorsal hindbrain; [3] the intracellular signaling pathways mediating the suppression of intake by hindbrain GLP-1 receptor activation. Understanding the physiological mechanisms, receptor populations and intracellular signaling pathways mediating the energy balance and glycemic effects of GLP-1 receptor activation has the potential to reveal novel insights for pharmaceutical drug developments aimed at preventing and treating obesity and Type II Diabetes Mellitus. PUBLIC HEALTH RELEVANCE: Basic science discoveries have identified specific brain chemical systems that can reduce food intake when stimulated. These discoveries are driving pharmaceutical developments aimed at preventing or treating obesity; however, to date, there are no effective drug treatments for obesity. A novel approach is taken here; we think that more progress could be made if basic research were to focus on understanding the natural physiological mechanisms, receptor populations, and signaling pathways of the hormone glucagon-like-peptide-1, providing insights into unexplored obesity drug treatment options.