DESCRIPTION (provided by applicant): Obesity is the main risk factor for developing type II diabetes (T2D), a major and growing public health problem. Elevated adiposity leads to central leptin and insulin resistance, which in turn can trigger changes in homeostatic neural circuitry in the hypothalamus. This can ultimately lead to the development of metabolic syndrome and T2D. Neurogenesis in the adult hypothalamic parenchyma is disrupted by high fat diet (HFD) and leptin deficiency, leading to a reduction in the number of anorexigenic POMC- expressing neurons. We have recently identified hypothalamic tanycytes as a second source of newborn neurons in adult hypothalamus. Our preliminary data suggests that while HFD and leptin deficiency stimulate tanycyte-derived neurogenesis, tanycyte-derived neurons promote weight gain in wildtype animals but inhibit weight gain in leptin-deficient mice. The studies proposed here aim to improve our understanding of how tanycyte-derived neurons regulate body weight, and to determine how dietary signals regulate tanycyte-derived neurogenesis. First, using genetic approaches, we plan to investigate the physiological consequences of selectively disrupting and enhancing tanycyte-derived neurogenesis. Second, we plan to investigate the molecular mechanisms by which both HFD-induced cytokines such as CNTF and leptin regulate tanycyte-derived neurogenesis. Finally, we propose to determine the exact identity of tanycyte-derived neurons and to identify their post-synaptic targets. We anticipate that these studies will ultimately assist in the design of novel therapies for treatment of obesity and T2D.

PUBLIC HEALTH RELEVANCE: Management of obesity is critical for treating type II diabetes (T2D), but less than 15% of individuals achieve lasting weight loss through diet and exercise alone. We have found that tanycytes in the hypothalamus generate new neurons that regulate body weight. We propose to determine exactly how these newly formed neurons regulate body weight, and how dietary signals control the formation of new hypothalamic neurons, with the goal of developing new treatments for obesity and T2D.