The ability of FGF21 to ameliorate signs of non-alcoholic fatty liver disease in mice depends on sex and diet

Consumption of high-calorie food leads to the development of obesity and non-alcoholic fatty liver disease (NAFLD). The pathogenesis of NAFLD depends on the composition of the diet. Administration of fibroblast growth factor 21 (FGF21) to obese mice improves metabolism and liver condition; however, the dependence of this effect on sex and diet composition has not been studied. Objective: To investigate the influence of sex on liver condition in mice with diet-induced obesity caused by different diets and on the ability of FGF21 to beneficially affect liver function. Obesity was induced in male and female C57BL/6J mice using a high-fat diet (HFD) or a cafeteria diet (DCaf). After obesity development, mice were administered FGF21 (1 mg/kg for 7 days), and the morphofunctional state and gene expression in the liver were assessed. When maintained on an HFD, hepatic steatosis was less severe in females than in males. FGF21 did not affect the lipid droplet area in individuals of either sex but exerted a sex-dependent influence on gene expression: in females, it reduced the expression of glycolysis and lipogenesis genes, preventing lipid accumulation, while in males, it reduced the expression of inflammation, apoptosis, and fibrosis genes, preventing the transition from steatosis to steatohepatitis. When maintained on a DCaf, pronounced steatosis developed in mice of both sexes. FGF21 reduced liver lipid content regardless of sex. However, only in females did FGF21 reduce the expression of the Cidec gene involved in lipid droplet formation and increase the number of apoptotic bodies. In males, the effect of FGF21 on lipid accumulation in the liver appeared to be mediated by its action on other tissues. Thus, in obese mice, sex differences in the severity of hepatic steatosis depended on the diet type and were observed only against the background of HFD. Administration of FGF21 led to a reduction in the total area of lipid droplets in the liver in mice of both sexes only against the background of pronounced steatosis induced by the DCaf. The influence of FGF21 on gene expression in the liver was sex-dependent, both against the background of HFD and DCaf.

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