Regulation of FGF21 Gene Expression by Nutritional Signals and Physical Activity in vivo and in vitro

Abstract

Fibroblast growth factor 21(FGF21) regulates glucose and lipid metabolism. However, the regulation of FGF21 expression by nutrients, hormones and physical activity is not fully understood. We sought to explore how nutritional signals and physical activity regulate FGF21 gene expression in liver and adipose tissue. In experiment 1, C57BL/6 male mice were fed a stock nonpurified diet (NP), a purified high‐carbohydrate (CHO) liquid diet, or the same diet with lipid emulsion (LE) for 4 weeks. Hepatic FGF21 gene expression was increased ~21‐fold in the high‐CHO group versus the control group. However, LE reversed FGF21 induction by the CHO diet in a dose‐dependent manner. By contrast, adipose FGF21 was not changed. In experiment 2, C57BL/6 male mice were randomly assigned to 3 groups: a low‐fat purified diet, a high‐fat purified diet, or high fat‐diet with voluntary running. After 16 weeks, FGF21 did not differ between low‐ and high‐fat diets; however, voluntary exercise dramatically reduced hepatic FGF21 expression, as compared to the other two groups. In human HepG2 liver cells that were cycled between 5.5 and 25 mM glucose, FGF21 was significantly decreased ~20‐fold by glucose starvation and increased ~2.5‐fold by glucose refeeding. In addition, insulin significantly induced FGF21, while glucagon had no effect. We conclude that FGF21 in liver is regulated by dietary CHO, insulin, and physical activity. NIH CA‐90214