Abstract 083: Divergent Metabolic and Cardiovascular Effects of FGF21

Abstract

Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone that regulates energy homeostasis. We previously demonstrated that FGF21 act in the brain to increase thermogenic sympathetic nerve activity (SNA), and that this effect required for the weight-reducing action of this hormone. However, the role of FGF21 in cardiovascular sympathetic control has not been investigated. To address this, we examined the effect of FGF21 on renal SNA recorded simultaneously with thermogenic brown adipose tissue (BAT) SNA in mice. In line with our previous findings, intravenous infusion of FGF21 (1mg/kg for 30 min) led to a significant increase in BAT SNA (182±33%, p<0.05), but not renal SNA (-35±16%). Intracerebroventricular administration of FGF21 (1 μg) that increased BAT SNA also failed to increase renal SNA (-14±28%) in mice. Next, we tested the effect of FGF21 on telemetry blood pressure and heart rate in mice. Chronic treatment with FGF21 (1mg/kg BID, IP) for 5 days led to a significant decrease in body weight (p=0.01), but caused no significant change in blood pressure (MAP: 3±3 mmHg vs 4±4 mmHg in vehicle control group, p=0.43) and heart rate (16±24 bpm vs 14±24 bpm in controls, p=0.5). Similarly, chronic treatment with the potent long-acting rhFGF21 analog (10mg/kg, SC) decreased body weight (p=0.002), but failed to alter blood pressure (p=0.14) and heart rate (p=0.25). Finally, we studied transgenic mice that overexpress FGF21 leading to ~5-10 fold higher circulating FGF21 than in the control mice. Interestingly, transgenic FGF21 mice displayed lower blood pressure (MAP: 104±1 vs 117±1 mmHg in controls, p<0.001) without change in heart rate (p=0.09). Consistent with the lower body weight (17.7± 0.8g vs 34.4± 1.3g in wild type controls), transgenic FGF21 mice displayed a 125% greater (p<0.001) baseline BAT SNA relative to controls whereas renal SNA was only 16% higher (p=0.02) in the transgenic mice. Together, our findings show contrasting effects of FGF21 on SNA controlling metabolism relative to blood pressure. The selective action of FGF21 may contribute to the differential sympathetic regulation of metabolism vs cardiovascular function.