The preference for high-calorie foods depends on sex and contributes to obesity development. Fibroblast growth factor 21 (FGF21) beneficially affects taste preferences and obesity, but its action has mainly been studied in males. The aim of this study was to compare the effects of FGF21 on food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with diet-induced obesity. Mice were injected with FGF21 or vehicle for 7 days. Body weight, choice between standard (SD) and high-fat (HFD) diets, blood parameters, and gene expression in white (WAT) and brown (BAT) adipose tissues, liver, muscles, and the hypothalamus were assessed. Compared to males, females had a greater preference for HFD; less WAT; lower levels of cholesterol, glucose, and insulin; and higher expression of Fgf21, Insr, Ppara, Pgc1, Acca and Accb in the liver and Dio2 in BAT. FGF21 administration decreased adiposity; blood levels of cholesterol, glucose, and insulin; hypothalamic Agrp expression, increased SD intake, decreased HFD intake independently of sex, and increased WAT expression of Pparg, Lpl and Lipe only in females. Thus, FGF21 administration beneficially affected mice of both sexes despite obesity-associated sex differences in metabolic characteristics, and it induced female-specific activation of gene expression in WAT.

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the A^y mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese A^y males and females. A^y mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.

We investigated the influence of sex and the age of obesogenic diet initiation on the obesity phenotypes at a later age. C57Bl mice started the Cafeteria Diet (CafD, with increased fat and carbohydrates, ad libitum, from 7 weeks of age (7CafD, pre-puberty) or 17 weeks of age (7CafD, post-puberty) while control C57Bl mice were fed regular chow. At 27 weeks of age, 7CafD males (n = 9) compared to 17CafD males (n = 7) had lower body weight, white adipose tissue (WAT) relative weight, and plasma cholesterol levels, and a higher expression of thermogenic genes in WAT and brown adipose tissue (BAT), and fatty acid oxidation (FAO) and insulin signalling genes in muscles. The 7CafD females (n = 8), compared to 17CafD females (n = 6), had higher plasma triglyceride levels and hepatic glycogen content, but lower insulin sensitivity and hepatic expression of FAO and insulin signalling genes. The 7CafD females, compared to 7CafD males, had more WAT, and a reduced expression of FAO genes in muscles and thermogenic genes in WAT. The 17CafD females, compared to 17CafD males, had lower plasma leptin and insulin levels, and higher insulin sensitivity and expression of insulin signalling genes in the liver and muscles. Thus, the initiation of the obesogenic diet before puberty led to a more adaptive metabolic phenotypes in males, and after puberty, in females.

Maternal diet and obesity (MO) may influence taste preferences and increase the susceptibility to obesity in offspring, but the impact of MO per se to these influences is poorly understood. We evaluated the influence of MO on food choice and susceptibility to obesity in offspring when mothers consumed a standard diet (SD). Mice with the Lethal yellow mutation (A^y/a) develop obesity consuming an SD. Metabolic parameters were assessed in pregnant and lactating A^y/a (obesity) and a/a (control) mothers. Metabolic response to the consumption of a sweet–fat diet (SFD: SD, lard, and sweet biscuits) and the choice of components of this diet were evaluated in their male and female offspring. Compared to control mothers, pregnant obese mothers had higher levels of insulin, leptin, and FGF21. MO increased food intake and liver expression of lipogenesis genes in male offspring consuming the SD. SFD consumption caused obesity development and insulin resistance, increased liver expression of glycolytic and lipogenesis genes, and affected hypothalamic expression of anorexigenic and orexigenic genes. In offspring of both sexes, MO had no effect on food choice and metabolic response to SFD intake. Therefore, when obese mothers consume a balanced diet, MO does not affect food choice and development of diet-induced obesity in offspring.