Alcoholic fatty liver is blunted by rFGF21 administration in mice lacking adipose FGFR1: The role of FGF21 in PPARα-mediated regulation of adipose tissue mass

Abstract

Fibroblast growth factor 21 (FGF21) is regulated by peroxisome proliferator activated receptor α (PPARα) in the liver. FGF21 regulates lipid metabolism via fibroblast growth factor receptor 1 (FGFR1). FGF21 protect against alcoholic fatty liver (AFL), however, FGF21 does not exert protective effect through liver FGFR1. We have previously shown that PPARα agonist WY-14,643 induces FGF21 and adipose atrophy but fails to protect against chronic ethanol-induced AFL in mice lacking adipose FGFR1. In this study we tested the direct role of the FGF21 in regulation of adipose tissue mass and ethanol induced-hepatic triglyceride (TG) accumulation in normal control (fgfr1^fl/fl) mice and in adipose FGFR1 knockout mice (fgfr1^adipoQ-cre). First, we tested whether WY-14,643 effects on adipose atrophy and AFL can be recapitulated in binge alcohol model. As in chronic model, adipose tissue mass and serum free fatty acid (FFA) were decreased by WY-14,643 in the fgfr1^adipoQ-cre mice but not in the fgfr1^fl/fl mice. However, in contrast to the chronic model, binge ethanol-induced AFL was blunted by WY-14,643 to a greater extent in the fgfr1^adipoQ-cre mice than in the fgfr1^fl/fl mice. Similarly, circulating FGF21 was elevated by binge ethanol to a greater extent in the fgfr1^adipoQ-cre mice than in the fgfr1^fl/fl mice on top of WY-14,643 treatment. Accordingly, we tested the involvement of the FGF21 in adipose atrophy and AFL. Consistent with FGFR1-dependent effects of WY-14,643 on adipose atrophy and AFL, recombinant mouse FGF21 (rFGF21) injection induced adipose atrophy, blunted AFL and serum TG elevation to a greater extent in the fgfr1^adipoQ-cre mice than in the fgfr1^fl/fl mice. These results indicated the consistency of adipose FGFR1 dependent effect of WY-14,643 and FGF21 in PPARα-mediated regulation of adipose tissue mass and fat mobilization from adipose tissues to the liver, suggesting that adipose tissues crosstalk with liver through an interaction between liver PPARα-FGF21 and adipose FGFR1 to maintain adipose tissue mass.

Keywords: Adipose atrophy; Fibroblast growth factor 21 (FGF21); Fibroblast growth factor receptor 1 (FGFR1); Lipid metabolism; Peroxisome proliferator-activated receptor-α (PPARα).