Low-Dose FGF-21 Administration Decreases Obesity-Induced Hepatic Steatosis, but Has No Effect on Inflammation in Mice

Pharmacologically, FGF-21 reduces body weight, increases insulin sensitivity, and reduces hepatic lipids in rodents. Preclinical studies suggest that FGF-21 may exert anti-inflammatory effects. We aimed to determine 1) whether endogenous FGF-21 provides protective effects against high-fat diet (HFD)-induced inflammation, and 2) whether low-dose administration of FGF-21 reverses HFD-induced inflammation and hepatic steatosis. In experiment #1, wild type (WT) and FGF-21^-/- mice (n=8/group) were fed a HFD for 15 weeks. RT-PCR analysis showed that despite weighing slightly less than the WT mice, the FFG-21^-/- mice were more susceptible to HFD-induced inflammation of the liver and white adipose tissue (WAT). To test whether administration of FGF-21 provides protection from HFD-induced inflammation, in Experiment #2, 20 male C57BL/6J mice were fed a HFD for 10 weeks. After 10 weeks of HFD feeding, mice were administered vehicle (saline + 0.1% BSA; n=10) or recombinant human FGF-21 (R and D Systems; n=10; 0.3 mg/kg/day) for 14 days via subcutaneous osmotic minipumps. There was no effect of FGF-21 administration on body weight. Histological analysis of WAT showed no effect of FGF-21 on adipocyte size, and no effect on crown-like structure number. Confirming this lack of effect of FGF-21 on inflammation, RT-PCR analyses of liver and WAT showed comparable mRNA expression of inflammatory markers, including Adgre1, Itgam, Itgax, Ccl2, Il1b, and Tnf in the vehicle- and FGF-21 treated groups. Despite having no effect on inflammation, FGF-21 significantly reduced fasting blood glucose levels. Histological evaluation of liver showed that low-dose FGF-21 administration improved nonalcoholic steatohepatitis score, attributed to decreased microvesicular steatosis.

In conclusion, endogenous FGF-21 confers some protection against obesity-induced inflammation, and low-dose FGF-21 administration decreases hepatic steatosis independent of changes in body weight.