Fibroblast Growth Factor 21 Action in the Brain Increases Energy Expenditure and Insulin Sensitivity in Obese Rats

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/day) was infused continuously for 2 weeks into the lateral cerebral ventricle of male Wistar rats rendered obese by high-fat feeding. Study end points 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 with vehicle, continuous intracerebroventricular 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 intracerebroventricular 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 central nervous system as a potentially important target for the beneficial effects of FGF21 in the treatment of diabetes and obesity.Fibroblast growth factor (FGF) 21 is a FGF family member produced by liver and other tissues that plays an important role in the control of energy balance and glucose metabolism (1). In addition, when administered at pharmacologic doses, FGF21 induces wide-ranging beneficial effects in animal models of obesity and diabetes (2). Specifically, in obese rodents, pharmacologic FGF21 treatment reduces body fat content and improves glucose tolerance, insulin sensitivity, and lipid parameters (both circulating and hepatic) (3–5). Consequently, FGF21 has emerged as a novel target for the treatment of obesity and associated metabolic dysfunction (2). FGF21-mediated weight loss appears to involve increased fat oxidation and metabolic rate with no change of food intake (3). Whether the insulin-sensitizing effects of FGF21 are dependent on reduced body fat or involve other, independent mechanisms has not been established. Interestingly, these insulin-sensitizing effects are attributable largely to enhanced insulin action in the liver (6), and yet recent evidence suggests that FGF21 regulates hepatic substrate metabolism via a mechanism that cannot be explained by a direct effect on hepatocytes (6).The diverse and indirect nature of these pharmacologic effects raises the possibility that at least some actions of FGF21 might be mediated centrally. This hypothesis is consistent with growing evidence implicating the hypothalamus and other regions of the central nervous system (CNS) in adaptive adjustments of insulin sensitivity triggered by changing levels of key hormones and nutrients in the circulation (7). To determine whether metabolic effects observed during systemic FGF21 treatment might involve a central site of action, we infused FGF21 into the brain of diet-induced obesity (DIO) rats at a low dose that does not leak into the circulation in detectable amounts.