PPARα agonist WY-14,643 induces adipose atrophy and fails to blunt chronic ethanol-induced hepatic fat accumulation in mice lacking adipose FGFR1

Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha) in liver. The PPAR alpha-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1adipoQ-cre) mice and corresponding normal control (fgfr1fl/fl) mice were fed with Lieber-DeCarli ethanol liquid diet for 3 weeks, liver triglyceride (TG) accumulation was increased in the fgfr1fl/fl mice to a greater extent than in the fgfr1adipoQ-cre mice. When PPAR alpha agonist WY14,643 was added in the liquid ethanol diet at 10 mg/L, the ethanol-induced liver TG accumulation was blunted in the fgfr1fl/fl mice but not in the fgfr1adipoQ-cre mice. There was no significant difference in WY-14,643induced fatty acid oxidation, ethanol metabolism, and oxidative stress between the fgfr1fl/fl and fgfr1adipoQ-cre mice. Interestingly, adipose atrophy was induced by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. Serum free fatty acid was also decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. These results suggest that WY-14,643 inhibits alcoholic fatty liver and regulates adipose tissue mass and fat mobilization from adipose tissues to liver in an adipocyte FGFR1-dependent manner.

Automated summary

FGF21 is mainly regulated by PPARα in liver, providing protection against ALD. While liver-specific FGFR1 abrogation had no effect on ALD, adipose tissues highly express FGFR1. In mice experiments, WY-14,643 inhibits alcoholic fatty liver through FGFR1-dependent regulation of adipose tissue mass and fat mobilization to the liver.