Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we determined whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Metabolic syndrome is a state of metabolic dysregulation that is characterized by obesity, hepatic steatosis, hyperlipidemia, atherosclerosis, and glucose intolerance (1). A key mechanism contributing to the development of metabolic syndrome is an elevation in the rate of hepatic fatty acid synthesis (2, 3). Hepatic fatty acid synthesis drives the synthesis of triacylglycerols that accumulate in the liver, blood, and adipose tissue. An elevation in hepatic fatty acid synthesis also promotes glucose intolerance, as accumulation of fatty acid metabolites in the liver suppresses the ability of insulin activate glycogen synthesis and inhibit gluconeogenesis (3). Accordingly, one approach to treating metabolic syndrome has been to manipulate the activity of signal transduction pathways that modulate hepatic fatty acid synthesis. For example, the beneficial effect of metformin on glucose tolerance in diabetic animals is mediated by a decrease in the rate of hepatic fatty acid synthesis (4). Metformin suppresses fatty acid synthesis by inhibiting the activity of acetyl-CoA carboxylase-␣ (ACC␣) 2 and decreasing the expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. Metformin also increases the rate of hepatic fatty acid oxidation, an effect that contributes to the improvement in glucose tolerance. Metformin-induced changes in hepatic fatty acid synthesis and fatty acid oxidation are mediated by an activation of AMP-activated protein kinase (AMPK). As metformin administration causes undesirable side effects, the identification of new signaling pathways that modulate hepatic fatty acid metabolism may lead to the development of more effective therapies for treating metabolic syndrome.Fibroblast growth factor-19 (FGF-19) was originally identified as a signal promoting the development of the inner ear in chick embryos (5). Subsequent studies have shown that FGF-19 and its mouse ortholog, FGF-15, also function in adult animals. For example, FGF-19/FGF-15 expressed in the small intestine acts as an enterohepatic hormone, mediating the inhibitory effects of intestinal bile acids on expression of hepatic cholesterol 7␣-hydroxylase (CYP7A1), a key regulatory step in the bile acid synthesis pathway (6, 7). FGF-19 also regulates carbohydrate and lipid metabolism in adult animals. Administration of recombinant human FGF-19 or transgenic expression of the human FGF-19 gene in obese/diabetic mice causes an increase in energy expenditure and a decrease in adipose tissue stores (8, 9). Treatment of obese/diabetic mice with FGF-19 also reduces serum and...