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) regulates lipid metabolism via fibroblast growth factor receptor 1 (FGFR1). FGF21 protects against alcoholic fatty liver, which is still observed in mice lacking liver FGFR1, suggesting the involvement of extra‐hepatic FGFR1 in mediating alcoholic fatty liver. We have previously shown that, in a chronic Lieber‐DeCarli model, the peroxisome proliferator‐activated receptor‐α (PPARα) agonist WY‐14,643 induced FGF21 and adipose atrophy but failed to protect against alcoholic fatty liver in mice lacking adipose FGFR1. In this study we tested the role of the FGF21 in regulation of adipose tissue mass and ethanol induced‐hepatic fat (triglyceride, TG) accumulation in mice lacking adipose FGFR1. In binge alcohol model, male adipose FGFR1 knockout mice (fgfr1adipoQ‐cre) and corresponding normal control (fgfr1fl/fl) mice were fed liquid control diet with or without 20 mg/L WY‐14,643 for 2 weeks followed by a binge ethanol gavage at 5 g/kg, adipose tissue mass and serum free fatty acid were decreased by WY‐14,643 in the fgfr1adipoQ‐cremice but not in the fgfr1fl/flmice. However, in contrast to the chronic model, the binge ethanol‐induced liver TG accumulation was blunted by WY‐14,643 to a greater extent in the fgfr1adipoQ‐cremice than in the fgfr1fl/flmice. Consistently, on top of WY‐14,643 feeding, circulating FGF21 was elevated by binge ethanol to a greater extent in the fgfr1adipoQ‐cre mice than in the fgfr1fl/fl mice. To test the involvement of the FGF21 in adipose atrophy and the less extent of hepatic fat accumulation in the fgfr1adipoQ‐cremice, recombinant mouse FGF21 (rFGF21) was injected intraperitoneally at 0.4 mg/kg to the 3‐week ethanol fed fgfr1adipoQ‐cre mice and fgfr1fl/fl mice during the last 10 days of the ethanol feeding. Consistent with FGFR1‐dependent effects of WY‐14,643 on adipose atrophy and liver fat accumulation, on the top of chronic ethanol diet, rFGF21 administration induced adipose atrophy, blunted liver TG accumulation and serum TG elevation to a greater extent in the fgfr1adipoQ‐cre mice than in the fgfr1fl/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.