FGF21 Action in the Brain Increases Energy Expenditure and Insulin Sensitivity in Obese Rats

  1. Michael W. Schwartz (mschwart{at}u.washington.edu)
  1. Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, WA


Objective: The hormone fibroblast growth factor 21 (FGF21) exerts diverse, beneficial effects on energy balance and insulin sensitivity when administered systemically to rodents with diet-induced obesity (DIO). The current studies investigate whether central FGF21 treatment recapitulates these effects.

Research Design and Methods: After preliminary dose-finding studies, either saline vehicle or recombinant human FGF21 (0.4 μg/d) was infused continuously for 2 wk into the lateral cerebral ventricle of male Wistar rats rendered obese by high-fat feeding. Study endpoints included measures of energy balance (body weight, body composition, food intake, energy expenditure and circulating and hepatic lipids) and glucose metabolism (insulin tolerance test, euglycemic-hyperinsulinemic clamp and hepatic expression of genes involved in glucose metabolism).

Results: Compared to vehicle, continuous intracerebroventricular (icv) infusion of FGF21 increased both food intake and energy expenditure in rats with DIO, such that neither body weight nor body composition was altered. Despite unchanged body fat content, rats treated with icv FGF21 displayed a robust increase of insulin sensitivity due to increased insulin-induced suppression of both hepatic glucose production and gluconeogenic gene expression, with no change of glucose utilization.

Conclusions: FGF21 action in the brain increases hepatic insulin sensitivity and metabolic rate in rats with DIO. These findings identify the CNS as a potentially important target for the beneficial effects of FGF21 in the treatment of diabetes and obesity.


    • Received December 22, 2009.
    • Accepted March 20, 2010.