Recent studies have revealed the importance of gut hormones as principal responders to nutrient status and as potential new therapeutics for treating the escalating obesity epidemic. Under the previous funding period, we discovered that the atypical fibroblast growth factor, FGF15, and its human ortholog, FGF19, are expressed and secreted from intestine as novel endocrine hormones in response to postprandial activation of the bile acid receptor FXR. In turn, FGF15/19 enters the hepatic portal circulation and governs bile acid synthesis and gallbladder filling. Studies have also shown pharmacologic administration of FGF15/19 markedly improves insulin sensitivity in rodent models of metabolic disease, whereas knocking out FGF15 expression in mice results in hyperinsulinemia and glucose intolerance. Together, these findings have linked postprandial uptake of bile acids in the gut with a novel FGF signaling pathway that plays a dual role in resetting key aspects of the digestive machinery and in mediating insulin-like effects in the liver following a meal. In this proposal, we seek to elucidate the molecular mechanisms that underlie these actions of FGF15/19 in the liver and to further characterize the repertoire of physiological effects FGF15/19 has on carbohydrate and lipid metabolism. In Aim 1, we will determine the molecular mechanism by which FGF15/19 regulates bile acid synthesis through its transcriptional repression of the gene encoding cholesterol 71-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. In Aim 2, we will explore the role the transcriptional coactivator PGC-11 has in mediating the insulin-sensitizing actions of FGF15/19. This aim is based on our unpublished finding that FGF15/19 causes a marked reduction in hepatic expression of PGC-11. In Aim 3 we will characterize the physiologic effects FGF15/19 has on carbohydrate and lipid metabolism by testing the hypothesis that FGF15/19 improves insulin sensitivity by inhibiting gluconeogenesis, thereby decreasing hepatic glucose production. These studies will provide fundamental insights into this newly characterized endocrine signaling pathway and examine its potential utility for the pharmacologic treatment of metabolic syndrome. PUBLIC HEALTH RELEVANCE: This proposal investigates the biological actions of FGF15/19, a relatively unexplored hormone that is secreted from the small intestine after a meal. Among its effects, FGF15/19 resets the digestive machinery, potentiates the actions of insulin, and causes weight loss in rodents. Insights from these studies may provide new clinical strategies for treating obesity, diabetes, and other forms of metabolic disease.