Fasting is often used for obesity correction but the “refeeding syndrome” limits its efficiency, and molecular mechanisms underlying metabolic response to different food availability are under investigation. Sex was shown to affect hormonal and metabolic reactions to fasting/refeeding. The aim of this study was to evaluate hormonal and transcriptional responses to fasting and refeeding in male and female C57Bl/6J mice. Sex asymmetry was observed both at the hormonal and transcriptional levels. Fasting (24 h) induced increase in hepatic Fgf21 gene expression, which was associated with elevation of plasma FGF21 and adiponectin levels, and the upregulation of expression of hepatic (Pparα, Cpt1α) and muscle (Cpt1β, Ucp3) genes involved in fatty acid oxidation. These changes were more pronounced in females. Refeeding (6 h) evoked hyperinsulinemia and increased hepatic expression of gene related to lipogenesis (Fasn) only in males and hyperleptinemia and increase in Fgf21 gene expression in muscles and adipose tissues only in females. The results suggest that in mice, one of the molecular mechanisms underlying sex asymmetry in hepatic Pparα, Cpt1α, muscle Cpt1β, and Ucp3 expression during fasting is hepatic Fgf21 expression, and the reason for sex asymmetry in hepatic Fasn expression during refeeding is male-specific hyperinsulinemia.

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.

In rodents, the most adequate model of human diet-induced obesity is obesity caused by the consumption of a sweet-fat diet (SFD), which causes more pronounced adiposity in females than in males. The aim of this work was to determine the sex-associated effect of SFD on the expression of genes related to carbohydrate-lipid metabolism in adult mice. For 10 weeks, male and female С57Bl mice were fed a standard laboratory chow (Control group) or a diet, which consisted of laboratory chow supplemented with sweet cookies, sunflower seeds and lard (SFD group). Weights of body, liver and fat depots, blood concentrations of hormones and metabolites, liver fat, and mRNA levels of genes involved in regulation of energy metabolism in the liver, perigonadal and subcutaneous white adipose tissue (pgWAT, scWAT) and brown adipose tissue (BAT) were measured. SFD increased body weight and insulin resistance in mice of both sexes. Female mice that consumed SFD (SFD females) had a greater increase in adiposity than SFD males. SFD females showed a decreased expression of genes related to lipogenesis (Lpl) and glucose metabolism (G6pc, Pklr) in liver, as well as lipogenesis (Lpl, Slca4) and lipolysis (Lipe) in pgWAT, suggesting reduced energy expenditure. In contrast, SFD males showed increased lean mass gain, plasma insulin and FGF21 levels, expressions of Cpt1α gene in pgWAT and scWAT and Pklr gene in liver, suggesting enhanced lipid and glucose oxidation in these organs. Thus, in mice, there are sex-dependent differences in adaptation to SFD at the transcriptional level, which can help to explain higher adiposity in females under SFD consumtion.

У мышей с мутацией lethal yellow (A y ) фармакологические эффекты фактора роста фибробластов 21 зависят от пола

The f ibroblast growth factor 21 (FGF21) synthesized in the liver, acting as a hormone, increases insulin sensitivity and energy expenditure. FGF21 administration has potent benef icial effects on obesity and diabetes in humans, cynomolgus monkey, and rodents. The therapeutic effects of FGF21 have been studied mainly in males. They are not always manifested in females, and they are accompanied by sex-specif ic activation of gene expression in tissues. We have suggested that one of the causes of sexual dimorphism in response to FGF21 is the effect of estradiol (E2). Currently, it is not known how estradiol modif ies the pharmacological effects of FGF21. The objective of this study was to study the inf luence of FGF21 on metabolic characteristics, food intake, and the expression of carbohydrate and fat metabolism genes in the liver, adipose tissue, and hypothalamus in female mice with alimentary obesity and low (ovariectomy) or high (ovariectomy + E2) blood estradiol level. In ovariectomized (OVX) females, the development of obesity was induced by the consumption of a high sweet-fat diet (standard chow, lard, and cookies) for 8 weeks. We investigated the effects of FGF21 on body weight, blood levels, food preferences and gene expression in tissues when FGF21 was administered separately or in combination with E2 for 13 days. In OVX obese females, FGF21, regardless of E2-treatment, did not affect body weight, and adipose tissue weight, or glucose tolerance but increased the consumption of standard chow, reduced blood glucose levels, and suppressed its own expression in the liver (Fgf21), as well as the expression of the G6pc and Acacα genes. This study is the f irst to show the modif ication of FGF21 effects by estradiol: inhibition of FGF21-inf luence on the expression of Irs2 and Pklr in the liver and potentiation of the FGF21-stimulated expression of Lepr and Klb in the hypothalamus. In addition, when administered together with estradiol, FGF21 exerted an inhibitory effect on the expression of Cpt1α in subcutaneous white adipose tissue (scWAT), whereas no stimulating FGF21 effects on the expression of Insr and Acacβ in scWAT or inhibitory FGF21 effect on the plasma insulin level were observed. The results suggest that the absence of FGF21 effects on body and adipose tissue weights in OVX obese females and its benef icial effect on food intake and blood glucose levels are not associated with the action of estradiol. However, estradiol affects the transcriptional effects of FGF21 in the liver, white adipose tissue, and hypothalamus, which may underlie sex differences in the FGF21 effect on the expression of metabolic genes and, possibly, in pharmacological FGF21 effects.