Glucagon Regulates Energy Balance via FGF-21 Signaling in the Brain

Abstract

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<0.01), with no observed differences in food intake or energy expenditure. Following chronic GcgR activation via the selective agonist IUB288, KlbδCNS mice exhibit a partial reduction in body weight (12%) in comparison to control mice (19%), suggesting that FGF-21 mediates glucagon’s anti-obesity properties through central action. Consistent with GcgR-stimulated, neuronal FGF-21 signaling, we found that neuronal activation, measured via immunohistochemical analysis of cFos expression, was increased in the SCN following IUB288 injection. Taken together, these data suggest that glucagon mediates part of its anti-obesity properties through FGF-21-KLB signaling in the SCN, and has implications for future treatments against obesity and the metabolic syndrome. 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..