Studying sex differences in responses to fibroblast growth factor 21 administration in obese mice consuming a sweet-fat diet

In animals, obesity caused by consumption of a sweet-fat diet (SFD) is the most adequate mouse model of human diet-induced obesity. Fibroblast growth factor 21 (FGF21) reduces body weight, beneficially affects taste preferences, and corrects glucose metabolism in obese mice. Sex is known to influence FGF21 effects in different models of diet-induced and hereditary obesity. In mice with SFD-induced obesity, the effects of FGF21 have been studied only in males. The aim of this study was to compare the effects of FGF21 on body weight, food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with SFD-induced obesity. Mice were fed with a diet consisting of standard chow, lard and cookies for 10 weeks, then they were injected with FGF21 (1 mg per 1 kg) or vehicle for 7 days. Body weight, weights of different types of food, blood parameters, glucose tolerance, gene and protein expression in the liver, gene expression in the white, brown adipose tissues, and the hypothalamus were assessed. FGF21 administration reduced body weight, did not alter total energy consumption, and activated orexigenic pathways of hypothalamus in mice of both sexes. However, sex dimorphism was found in the realization of the orexigenic FGF21 action at the transcriptional level in the hypothalamus. Metabolic effects of FGF21 were also sex-specific. Only in males, FGF21 exerted beneficial antidiabetic action: it reduced fatty acid and leptin plasma levels, improved glucose-tolerance, and upregulated hepatic expression of Ppargc1, Fasn, Accα, involved in lipid turnover, gene Insr and protein glucokinase, involved in insulin action. Only in obese females, FGF21 induced preference of standard diet to sweet food. Thus, in mouse model of obesity induced by consumption of a sweet-fat diet, the catabolic effect of FGF21 was not sex-specific and hormonal, transcriptional and behavioral effects of FGF21 were sex-specific. These data suggest elaboration of different approaches to use FGF21 analogs for correction of metabolic consequences of obesity in different sexes.