Fibroblast growth factor-19 action in the brain reduces food intake and body weight and improves glucose tolerance in male rats

Abstract

Fibroblast growth factor-19 (FGF19) and its rodent ortholog, FGF15, are hormones produced in the distal small intestine and secreted into the circulation after a meal. In addition to controlling the enterohepatic circulation of bile acids, FGF15/19 also regulates systemic lipid and glucose metabolism. In these experiments we investigated the hypothesis that, like other gut-derived postprandial hormones, FGF15/19 can act in the central nervous system to elicit its metabolic effects. We found that FGF-receptors 1 and 4 are present in rat hypothalamus, and that their expression was reduced by up to 60% in high-fat fed rats relative to lean controls. Consistent with a potential role for brain FGF15/19 signaling to regulate energy and glucose homeostasis, and with a previous report that intracerebroventricular (i.c.v.) administration of FGF19 increases energy expenditure, we report that acute i.c.v. FGF19 reduces 24-h food intake and body weight, and acutely improves glucose tolerance. Conversely, i.c.v. administration of an FGF-receptor inhibitor increases food intake and impairs glucose tolerance, suggesting a physiological role for brain FGF receptor signaling. Together, these findings identify the central nervous system as a potentially important target for the beneficial effects of FGF19 in the treatment of obesity and diabetes.

Fig. 1.

FGFR mRNA expression in hypothalamus of lean and DIO rats. Both FGFR1 (panel A) and FGFR4 (panel B) mRNAs were expressed in whole rat hypothalamus. A, The expression of FGFR1 was lower in the hypothalamus of high-fat diet-fed rats relative to lean controls (two-way ANOVA, P < 0.001; Tukey), regardless of whether the rats were killed in the fed state or after a 48-h fast. B, The expression of FGFR4 was lower in the hypothalamus of high-fat diet-fed rats relative to lean controls, and this was more apparent among rats killed in the fed state (two-way ANOVA, P < 0.001; Tukey) (n = 6-8 per group; *, P < 0.05; **, P < 0.01).

Fig. 2.

Infusion of FGF19 directly into the brain reduces food intake and body weight. In two independent experiments conducted in different cohorts of chow-fed rats (A–C[b]), infusion of FGF19 directly into the i3vt elicited a reduction in food intake over 24 h (RM ANOVA, P < 0.05; Tukey), accompanied by a reduction in body weight (t test). D, The same dose of FGF19, given i3vt, was also sufficient to reduce food intake over 24 h in rats maintained on a high-fat diet for 6 wk (RM ANOVA, P < 0.01; Tukey) and to E, significantly reduce body weight, relative to vehicle (VEH)-treated controls (t test, P < 0.05) (n = 5-9 per group; **, P < 0.01; *, P < 0.05).

Fig. 3.

Infusion of an FGFR inhibitor directly into the brain increases food intake. In two independent experiments conducted in different cohorts of chow-fed rats, infusion of the FGFR inhibitor PD173074 increased 24-h food intake (RM ANOVA, P < 0.05; Tukey) (n = 4-7 per group; *, P < 0.05). VEH, Vehicle. **, P < 0.01.

Fig. 4.

CNS FGFR signaling regulates glucose tolerance. In two independent experiments conducted in different cohorts of weight-matched chow-fed rats (A–E), infusion of FGF19 directly into the i3vt improved glucose tolerance, as measured by the time course (RM ANOVA, P < 0.05; Tukey) (A and C) or by the area under the curve (AUC, t tests) (B and D). E, This was not associated with differences in plasma insulin (RM ANOVA, P > 0.05). F, i3vt infusion of an FGFR inhibitor impaired glucose tolerance, as measured by the time course (RM ANOVA, P < 0.05; Tukey), G, Area under the curve [t test, nonsignificant (ns) (n = 3-7 rats per group; ***, P < 0.001; **, P < 0.01; *, P < 0.05].VEH, Vehicle.