Abstract
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.
Highlights
Fibroblast Growth Factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism
The fasting-induced increase in circulating FGF21 levels was more pronounced in females (Fig. 1A), which was reversed by refeeding in the mice of both sexes
The new finding of our study is demonstration of a female-specific activation of FGF21 signaling in response to the natural physiological states fasting and refeeding
Summary
Fibroblast Growth Factor-21 (FGF21) is a circulating hepatokine that beneficially affects carbohydrate and lipid metabolism. The liver is the main site of the production and release of FGF21 into the blood. Hepatic Fgf expression is under the control of peroxisome proliferator–activated receptor α (PPARα) (Badman et al, 2007; Inagaki et al, 2007; Fisher and Maratos-Flier, 2016). In WAT and BAT, expression of the Fgf gene is activated by PPARα and PPARγ (Hondares et al, 2011). WAT (Fisher et al, 2010) and BAT (Fisher et al, 2012) are known target tissues of FGF21 action
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