Metabolic responses to intermittent hypoxia are regulated by sex and estradiol in mice

The roles of sex and sex-hormones on the metabolic consequences of intermittent hypoxia ( IH, a reliable model of sleep apnea) are unknown. We used intact male or female mice and ovariectomized (OVX) females treated with vehicle (Veh) or estradiol (E-2) and exposed to normoxia (Nx) or IH (6% O-2, 10 cycles/h, 12 h/day, 2 wk). Mice were then fasted for 6 h, and we measured fasting glucose and insulin levels and performed insulin or glucose tolerance tests ( ITT or GTT). We also assessed liver concentrations of glycogen, triglycerides (TGs), and expression levels of genes involved in aerobic or anaerobic metabolism. In males, IH lowered fasting levels of glucose and insulin, slightly improved glucose tolerance, but altered glucose tolerance in females. In OVX-Veh females, IH reduced fasting glucose and insulin levels and strongly impaired glucose tolerance. E-2 supplementation reversed these effects and improved homeostasis model assessment of beta-cell function ( HOMA-beta), a marker of pancreatic glucose-induced insulin released. IH decreased liver TG concentration in males and slightly increased glycogen in OVX-Veh females. Liver expression of glycolytic (Ldha) and mitochondrial (citrate synthase, Pdha1) genes was reduced by IH in males and in OVX-Veh females, but not in intact or OVX-E-2 females. We conclude that 1) IH reduced fasting levels of glycemia in males and in ovariectomized females. 2) IH improves glucose tolerance only in males. 3) In females IH decreased glucose tolerance, this effect was amplified by ovariectomy, and reversed by E-2 supplementation. 4) During IH exposures, E-2 supplementation appears to improve pancreatic beta cells functions. NEW & NOTEWORTHY We assessed fasting glycemic control, and tolerance to insulin and glucose in male and female mice exposed to intermittent hypoxia. IH improves glucose tolerance in males but had opposite effects in females. This response was amplified following ovariectomy in females and prevented by estradiol supplementation. Metabolic consequences of IH differ between males and females and are regulated by estradiol in female mice.