Sexual Dimorphism in Control of Heart Failure in Insulin Resistance.

The incidence of cardiovascular diseases (CVD) is highly associated with type 2 diabetes (T2D). Women at an early age show reduced incidence of CVD and improved insulin sensitivity compared to men, but these disparities disappear during postmenopausal. Thus, ovary and ovarian hormone, such as estrogen, are expected to protect from these diseases. This study aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism upon loss-of-function of cardiac IRS1 and IRS2 in mice and investigate the underlying mechanisms. We found that all male heart-specific IRS1 and IRS2 double knock-out (H-DKO) mice died of heart failure (HF) at 6-8 weeks with severely impaired energy metabolism. However, all female H-DKO mice survived more than 1 year and showed improvement in energy metabolism. Removal of ovaries in H-DKO female mice led to cardiac dysfunction, disruption of energy metabolism, and ultimately death. However, E supplement significantly improved cardiac function, enhanced energy metabolism, and prolonged the lifespan in both male and OVX female H-DKO mice. Finally, we provided evidence that the protective effect of E is partially mediated through activation of Akt-Foxo1 signaling in H-DKO heart. These results show that estrogen protects mice from heart insulin resistance induced cardiomyopathy. This study indicates that estrogen signaling could be a potential target to prevent insulin resistance induced heart dysfunction in humans. Estrogen signaling is mediated through estrogen receptors, such as estrogen receptor (ER) α, ERβ, and membrane estrogen receptor (GPER). In the future, we will further decipher the role of estrogen receptors in estrogen mediated protection against cardiac dysfunction during insulin resistance.