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.

Obesity during pregnancy has been shown to increase the risk of metabolic diseases in the offspring. However, the factors within the maternal milieu which affect offspring phenotypes and the underlying mechanisms remain unknown. The adipocyte hormone leptin plays a key role in regulating energy homeostasis and is known to participate in sex‐specific developmental programming. To examine the action of leptin on fetal growth, placental gene expression and postnatal offspring metabolism, we injected C57BL mice with leptin or saline on gestational day 12 and then measured body weights (BWs) of offspring fed on a standard or obesogenic diet, as well as mRNA expression levels of insulin‐like growth factors and glucose and amino acid transporters. Male and female offspring born to leptin‐treated mothers exhibited growth retardation before and a growth surge after weaning. Mature male offspring, but not female offspring, exhibited increased BWs on a standard diet. Leptin administration prevented the development of hyperglycaemia in the obese offspring of both sexes. The placentas of the male and female foetuses differed in size and gene expression, and leptin injection decreased the fetal weights of both sexes, the placental weights of the male foetuses and placental gene expression of the GLUT1 glucose transporter in female foetuses. The data suggest that mid‐pregnancy is an ontogenetic window for the sex‐specific programming effects of leptin, and these effects may be exerted via fetal sex‐specific placental responses to leptin administration.

Fibroblast growth factor-21 (FGF21) beneficially affects carbohydrate and lipid metabolism. Previously, a sex-specific activation of Fgf21 expression was observed in humans and animals with metabolic diseases. It is unknown whether the sex differences in the Fgf21 expression are manifested in response to the natural physiological situations of fasting and refeeding. The aim of this work was to determine liver, White Adipose Tissue (WAT) and Brown Adipose Tissue (BAT) expression of genes related to FGF21 signaling in response to 24 h fasting, 6 h refeeding (after 24 h fasting) and Diet-Induced Obesity (DIO) in C57Bl mice of both sexes. Obesity was induced by the consumption of palatable food for 10 weeks. mRNA levels of peroxisome proliferator-activated receptor-a and-γ (Pparα, Pparγ), FGF21 (Fgf21), coactivator of FGF receptors (Klb) and transcriptional coactivator (Pgc-1α) were measured by RT-PCR. The study showed that the fasting-induced increases in hepatic Fgf21 gene expression and circulating FGF21 levels, as well as refeeding-induced increases in local WAT and BAT Fgf21 gene expression, were biased toward females. DIO-induced increase in circulating FGF21 levels, as well as in Fgf21 gene expression in the liver and BAT, were biased toward males. Considering that FGF21 is a novel metabolic regulator of energy homeostasis, sex differences in the responses to anabolic and catabolic stimulus could have translational implications for novel therapeutic outcomes.

FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay 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 Ay males and females. Ay 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.

Obesity during pregnancy increases the risk of obesity in offspring. To correct the offspring development in obese mothers, it is necessary to reveal the molecular mechanisms that mediate the influence of the maternal environment on the offspring ontogenesis. Leptin levels increase with obesity. In C57Bl mice, the Ау mutation is associated with elevated blood levels of leptin in pregnant females and exerts a gender-specific effect on the metabolic phenotype of mature offspring. Aim: to study the influence of Ау mutation on sensitivity to diet-induced obesity in male and female offspring, on fetal and placental weight and on the expression of genes in the placentas of the fetuses of different sexes. Body weight and food intake on a standard and an obesogenic diet, fetal and placental weights on pregnancy days 13 and 18, and gene expression of glucose transporters (GLUT1, GLUT3), neutral amino acid transporters (SNAT1, SNAT2, SNAT4), insulin-like growth factor 2 IGF2 and its receptor IGF2R were measured in male and female offspring of и ɑ/ɑ (control) and Ау/ɑ mothers. Ay mutation influenced the body weight only in male offspring, which consumed a standard diet, and did not influence obesity development in both male and female offspring. The weight of fetuses and placentas in Ау/ɑ as compared to ɑ/ɑ  females was reduced on day 13 of pregnancy and was not different on day 18. On day 13 of pregnancy, the mRNA levels of the examined genes did not differ in placentas of male and female fetuses in ɑ/ɑ  females. In Ау/ɑ females, the gene expression of GLUT1, GLUT3, SNAT1 and SNAT4 was reduced in female placentas compared to male placentas. The results suggest that the sex-specific transcription response of placentas to elevated leptin levels in pregnant Ау/ɑ females can mediate the gender-specific impact of Ау mutation on the offspring metabolism in postnatal life.