Hui Yan1,2, Wanbao Yang1, Fenghua Zhou1, Quan Pan1, Kimberly Allred1, Clinton Allred1, Yuxiang Sun1, David Threadgill3, David Dostal4,5, Carl Tong4, Shaodong Guo1. 1. Department of Nutrition, College of Agriculture and Life Sciences (H.Y., W.Y., F.Z., Q.P., K.A., C.A., Y.S., S.G.), Texas A&M University, College Station. 2. Key Laboratory of Animal Disease-Resistant Nutrition, Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu, China (H.Y.). 3. Department of Physiology and Pharmacology, School of Veterinary Medicine and Biomedical Science (D.T.), Texas A&M University, College Station. 4. Department of Medical Physiology, School of Medicine (D.D., C.T.), Texas A&M University, College Station. 5. Central Texas Veterans Healthcare System, Temple (D.D.).
Abstract
BACKGROUND: Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance. METHODS: Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively. RESULTS: All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades. CONCLUSIONS: These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.
BACKGROUND: Type 2 diabetes (T2D) is a high-risk factor for incident of cardiovascular diseases. Women at young ages show a reduced incidence of both T2D and cardiovascular diseases compared with men, but these disparities disappear in postmenopausal women versus age-matched men. Thus, ovaries and ovarian hormones, such as estrogen, are expected to protect from T2D and cardiovascular diseases. In this study, we aimed to investigate the role of ovaries and ovarian hormone estrogen in cardiac function and energy metabolism using the cardiac IRS (insulin receptor substrate) 1 and IRS2 double genes knockout mice that mimic cardiac insulin resistance. METHODS: Control and heart-specific IRS1/2 double genes knockout mice were treated with placebo or 17β-estradiol (E2) pellets, respectively, through subcutaneous implantation. Female mice were subjected to a bilateral ovariectomy surgery to remove endogenous E2. The cardiac function and energy metabolism were determined using echocardiography and indirect calorimeter, respectively. RESULTS: All male heart-specific IRS1/2 double genes knockout mice died of heart failure at 6 to 8 weeks as we previously described (Qi et al), but all female heart-specific IRS1/2 double genes knockout mice survived >1 year. Removal of ovaries in heart-specific IRS1/2 double genes knockout female mice resulted in cardiac dysfunction, and ultimately animal death. However, E2 supplementation prevented the dilated cardiomyopathy, improved cardiac function and energy metabolism, and enhanced lifespan in both male and ovariectomy female mice deficient for cardiac IRS1 and IRS2 genes, largely owing to the activation of Akt (protein kinase B)-Foxo1 (O1 class of forkhead/winged helix transcription factor) signaling cascades. CONCLUSIONS: These results show that estrogen protects mice from cardiac insulin resistance-induced diabetic cardiomyopathy. This may provide a fundamental mechanism for the gender difference for the incidence of both T2D and cardiovascular diseases. This study highlights that estrogen signaling could be a potential target for improving cardiac function and energy metabolism in humans with T2D.
Entities:
Keywords:
diabetic cardiomyopathy; energy metabolism; estradiol; estrogen; insulin resistance
Authors: Christian Riehle; Eric T Weatherford; Nicholas S McCarty; Alec Seei; Bharat P Jaishy; Rajkumar Manivel; Paolo Galuppo; Chantal Allamargot; Tariq Hameed; Ryan L Boudreau; Johann Bauersachs; Robert M Weiss; E Dale Abel Journal: Mol Cell Biol Date: 2022-09-20 Impact factor: 5.069