Project Summary / Abstract Obesity is a major contributor to the epidemic of metabolic diseases including dyslipidemia, cardiovascular disease, and type II diabetes. Numerous studies suggest that increasing energy expenditure can effectively decrease body weight. However, no current therapeutic compounds safely or selectively activate energy expenditure. The endocrine hormone fibroblast growth factor 21 (FGF21) decreases body weight during obesity by increasing energy expenditure without affecting physical activity. Moreover, FGF21 potently decreases both fat and body mass in obese animals and human patients. However, the mechanism for FGF21-mediated increases in energy expenditure has not been identified. Work from our lab and others have demonstrated that FGF21 acts in the central nervous system to promote weight loss. In addition, several lines of evidence suggest that FGF21 requires intact signaling from the adipose-derived hormone, leptin, to elicit its full effects on driving weight loss. Finally, our preliminary data demonstrates that the obligate FGF21 co- receptor, β-klotho, is expressed in the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH), primary sites of leptin action in the brain, and that leptin activates signaling in β-klotho-expressing cells in the VMH and ARC. Thus, we hypothesize that FGF21 signals, at least in part, to leptin-sensitive cells in the VMH and/or ARC to modulate energy expenditure. This proposal employs novel genetic mouse models, chemogenetic manipulation of neurons, and pharmacological approaches to investigate the crosstalk between FGF21 and leptin signaling in the central control of energy homeostasis. Through these studies we aim to identify novel therapeutic targets for the treatment of obesity and obesity-associated disorders.