Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 ± 0.06 liters O₂/h·kg^0.75 (vehicle) vs. 1.93 ± 0.05 liters O₂/h·kg^0.75 (FGF19); P < 0.001] and decreased respiratory quotient [0.82 ± 0.01 (vehicle) vs. 0.80 ± 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 ± 0.05 g/mouse·d), FGF19-treated mice lost weight (−0.13 ± 0.03 g/mouse·d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.