Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats

Abstract

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 microg/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.

FIG. 1.

Effect of central hFGF21 infusion on energy homeostasis in DIO rats. Percent body weight change (A), body composition (B), daily food intake (C), cumulative food intake (D), Vo₂ (E), and energy expenditure (F) in adult male rats with DIO (n = 6 per group) receiving continuous intracerebroventricular infusion of either hFGF21 (0.04 and 0.40 μg/day) or vehicle. For clarity, Vo₂ and energy expenditure data in E and F are presented as 3-h averages over three consecutive 12-h dark (D1–3) and two 12-h light (L1–2) cycles. *P < 0.05 vs. vehicle (Veh).

FIG. 2.

Central infusion of hFGF21 improves insulin sensitivity in DIO rats. Percent basal blood glucose levels (A), inverse area under the curve (B) during ITT, 4-h fasted blood glucose (C), plasma insulin levels (D), hepatic fat (E), and glycogen content (F) obtained from male Wistar rats with DIO (n = 6 per group) that received continuous intracerebroventricular infusion of either hFGF21 (0.40 μg/day) or vehicle for 2 weeks. Glucose infusion rate (GIR) (G) and arterial glucose levels (H) were measured during the euglycemic-hyperinsulinemic clamp on day 7 of intracerebroventricular infusion in separate groups of rats. *P < 0.05 vs. vehicle (Veh).

FIG. 3.

Central infusion of hFGF21 improves insulin sensitivity by increasing insulin-mediated suppression of endogenous glucose production. Rate of endogenous glucose appearance (Endo R_a) during the basal (□) and clamp (■) periods (A), percent suppression of hepatic glucose production (B), rate of glucose disposal during the basal and clamped periods (C), and percent increase in glucose utilization (D) during euglycemic-hyperinsulinemic clamps performed during continuous intracerebroventricular infusion of hFGF21 (0.40 μg/day) or vehicle as in Fig. 2. *P < 0.05 vs. vehicle (Veh).

FIG. 4.

Effect of central hFGF21 infusion on hepatic genes involved in gluconeogenesis and lipid metabolism. Hepatic levels of mRNA encoding gluconeogenic and lipid metabolic genes measured in either the presence (e.g., after the clamp) (A) or absence of hyperinsulinemia (e.g., after a 4-h fast) (B) in rats (n = 6–7 per group) receiving continuous intracerebroventricular infusion of hFGF21 (0.40 μg/day) or vehicle. *P < 0.05 vs. vehicle (Veh).

FIG. 5.

Effect of central hFGF21 infusion on energy homeostasis and glucose metabolism in lean rats. Percent body weight change (A), cumulative food intake (days 5–7) (B), and results obtained during an IPGTT, including percent change from basal blood glucose levels (C) and area under the curve (AUC) (D) in chow-fed adult male rats (n = 4 per group) receiving continuous intracerebroventricular infusion of either hFGF21 (0.40 μg/day) or vehicle for 7 days *P < 0.05 vs. vehicle (Veh).