Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon-receptor (GcgR) signaling are promising for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of another fasting hormone, Fibroblast Growth Factor 21 (FGF-21), also known to be involved in regulating energy balance. We have recently observed that mice deficient for liver FGF-21 (FGF-21δLiver) are partially resistant to the anti-obesity effects of GcgR agonism, clearly implicating hepatic FGF-21 as an essential component of the glucagon’s weight-loss effects. FGF-21 signals through an obligate co-receptor (βKlotho, Klb), with expression limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. As the hypothalamus has known roles in regulating energy balance, we hypothesized that the anti-obesity action of the glucagon-FGF-21 system signals through a central mechanism. Mice deficient for neuronal Klb (KlbδCNS) are less susceptible to diet-induced obesity than wild type mice (P Disclosure S. Nason: None. T. Kim: None. J.P. Antipenko: None. J. Paul: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..