Dual effects of fibroblast growth factor 21 on hepatic energy metabolism.

Andrew C Adams,Alexei Kharitonenkov,Ricardo J Samms,Tamer Coskun,Kostas Tsintzas,Francis J P Ebling,Scott Cooper,Michelle Murphy,Paul Emmerson,Maxine J Fowler

doi:10.1530/joe-15-0334

Abstract

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg per day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through β-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.

Highlights

Fibroblast growth factor 21 (FGF21) is an endocrine member of the fibroblast growth factor superfamily that plays a key role in the regulation of carbohydrate and fatty acid metabolism (Kharitonenkov & Adams 2014).The primary physiological role of FGF21 is reported to occur during the adaptive response to starvation in rodents (Markan et al 2014)
In animals chronically treated with FGF21 there was a progressive decrease in body weight during the first 6 days of the infusion period, after which body weight became relatively stable (Fig. 1A)
At the end of the 14-day treatment period body weight was decreased by 10% (P!0.05) in animals treated with FGF21 when compared to vehicle-treated controls at the end of the 14-day treatment period (Fig. 1A)

Summary

Introduction

Fibroblast growth factor 21 (FGF21) is an endocrine member of the fibroblast growth factor superfamily that plays a key role in the regulation of carbohydrate and fatty acid metabolism (Kharitonenkov & Adams 2014). The primary physiological role of FGF21 is reported to occur during the adaptive response to starvation in rodents (Markan et al 2014). Ñ 2015 Society for Endocrinology Printed in Great Britain FGF21 is being evaluated as a potential treatment for both obesity and diabetes and their associated comorbidities (Gaich et al 2013, Gimeno & Moller 2014)

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