Project Summary Over the past 3 decades, obesity and type 2 diabetes (T2D) have emerged as among the most common and costly chronic diseases confronting modern society. Treatment outcomes for patients affected with obesity or T2D have shown minimal improvement due to the absence of non-surgical medical treatments that have sustained efficacy. Therefore, an urgent need for new, more effective treatment options therefore exists, and strategies targeting the brain have important potential to meet this need. As one example of relevant preclinical work, our group has recently shown that signaling in the brain by exogenous administration of members of the fibroblast growth factor (FGF) family produces potent weight-loss and anti-diabetic effects. Our K08 proposal focused on the integrated central and peripheral mechanisms underlying the sustained anti-diabetic action of exogenous FGF1 in rodent models of obesity and T2D. In this application, we propose a parallel line of studies that will investigate the role of endogenous hypothalamic FGF1 signaling in the regulation of energy and glucose homeostasis. We have recently found that FGF1 is endogenously expressed by tanycytes and cells distributed in a number of key hypothalamic areas implicated in the control of body weight and glucose. Further, we have observed that endogenous hypothalamic FGF1 expression is regulated fasting and refeeding and in preliminary studies that deleting FGF1 from either hypothalamic neurons or tanycytes induces weight gain and glucose intolerance on chow diet. These data support the premise that endogenous hypothalamic FGF1 signaling plays a physiologic role in the regulation of energy and glucose homeostasis. We will investigate this hypothesis by determining the specific hypothalamic nuclei and cell types that express FGF1, identify which of these populations respond to acute and chronic changes in metabolic status and diet, and the extent to which disrupting endogenous hypothalamic FGF1 signaling is sufficient to promote the development of obesity and glucose intolerance. The data obtained from these investigations will form the basis of a new line of research centered on endogenous hypothalamic FGF1 signaling as a novel target to treat obesity and T2D.