Type 2 diabetes (T2D) and obesity are leading causes of mortality and are associated with the Western lifestyle, which is characterized by excessive nutritional intake and lack of exercise. A central player in the pathophysiology of these diseases is the nuclear hormone receptor (NHR) PPARγ, a lipid sensor and master regulator of adipogenesis. PPARγ is also the molecular target for the Thiazolidinedione (TZD)-class of insulin sensitizers, which command a large share of the current oral anti-diabetic drug market. Despite their efficacy in glycemic control, TZDs are associated with various adverse side effects, including weight gain, edema, and liver and cardiovascular toxicity, which limits their clinical use. During my postdoctoral research in the laboratory of dr Ronald M. Evans, at The Salk Institute, I have developed a novel screening tool for the functional analysis of complex transcriptional pathways. Using this technology, we have identified Fibroblast Growth Factor 1 (FGF1) as a novel target of PPARγ. In experiments with FGF1 knockout mice, we further demonstrated that these mice develop high-fat diet induced insulin resistance and hepatic steatosis, underscoring its significance in the development of T2DM. The studies proposed here aim to investigate the pharmacologic effects of FGF1 on energy metabolism and the development of T2D. This novel pathway defines a previously unrecognized mechanism for the insulin sensititizing actions of TZDs. Therapeutic targeting of FGF1 could serve as an improved strategy for the treatment of T2D, eliminating some of the adverse effects of TZDs that are mediated through direct activation of PPARγ.
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