Sex Differences in Liver, Adipose Tissue, and Muscle Transcriptional Response to Fasting and Refeeding in Mice

Abstract

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.

Physiologic Responses to Dietary Sulfur Amino Acid Restriction in Mice Are Influenced by Atf4 Status and Biological Sex

“…During dietary SAAR, WT males showed a prominent hepatic ISR signature alongside large changes in metabolism and body composition, whereas females showed moderate to minimal changes in most measured variables. These findings are in agreement with other models of dietary restriction that show metabolic outcomes to be influenced by biological sex ( 78 – 81 ). Furthermore, evidence for androgen receptor involvement in nutrient stress signaling is reported in certain types of cancer ( 82 , 83 ).…”

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures

“…Furthermore, albeit only nominally significant, sex-varying associations of methylation at cg00574958 with small and very small VLDLs could partially explain reported lower concentration and average size of circulating VLDLs in women compared to men [ 50 ]. In line with prior observations of sex-specific effects for Cpt1a in rodent lipid metabolism [ 51 , 52 ], our results suggest a link between hypermethylation at cg00574958 and anti-atherogenic traits, possibly emphasized in females, further supporting that hypermethylation at this CpG site might be linked to healthier metabolic outcomes.…”

Use of human PBMC to analyse the impact of obesity on lipid metabolism and metabolic status: a proof-of-concept pilot study

“…Overweight-obesity did not affect mRNA levels of this gene, however, sex differences were observed. NW men presented higher gene expression levels of PPARG than those of NW women, and the same occurred for FASN expression, as has been also reported in adipose tissue of rodents 41 , 42 .…”