title: Estrogen receptor alpha activation enhances mitochondrial function and systemic metabolism in high-fat-fed ovariectomized mice.
abstract: Estrogen impacts insulin action and cardiac metabolism, and menopause dramatically increases cardiometabolic risk in women. However, the mechanism(s) of cardiometabolic protection by estrogen remain incompletely understood. Here, we tested the effects of selective activation of E2 receptor alpha (ERα) on systemic metabolism, insulin action, and cardiac mitochondrial function in a mouse model of metabolic dysfunction (ovariectomy [OVX], insulin resistance, hyperlipidemia, and advanced age). Middle-aged (12-month-old) female low-density lipoprotein receptor (Ldlr)(-/-) mice were subjected to OVX or sham surgery and fed "western" high-fat diet (WHFD) for 3 months. Selective ERα activation with 4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl) (PPT), prevented weight gain, improved insulin action, and reduced visceral fat accumulation in WHFD-fed OVX mice. PPT treatment also elevated systemic metabolism, increasing oxygen consumption and core body temperature, induced expression of several metabolic genes such as peroxisome proliferator-activated receptor gamma, coactivator 1 alpha, and nuclear respiratory factor 1 in heart, liver, skeletal muscle, and adipose tissue, and increased cardiac mitochondrial function. Taken together, selective activation of ERα with PPT enhances metabolic effects including insulin resistance, whole body energy metabolism, and mitochondrial function in OVX mice with metabolic syndrome.
authors: Center for Metabolic and Bioenergetics Research, Houston Methodist Research Institute and Weill Cornell Medical College, Houston, Texas Houston Methodist Research Institute, Houston, Texas Houston Methodist Department of Medicine, Houston, Texas.
authors: Dale J
authors: DJ
authors: Hamilton
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Laurie J
authors: LJ
authors: Minze
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Tanvi
authors: T
authors: Kumar
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Tram N
authors: TN
authors: Cao
authors: Houston Methodist Research Institute, Houston, Texas.
authors: Christopher J
authors: CJ
authors: Lyon
authors: University of Kansas Medical Center, Kansas City, Kansas.
authors: Paige C
authors: PC
authors: Geiger
authors: Ohio State University, Columbus, Ohio.
authors: Willa A
authors: WA
authors: Hsueh
authors: Center for Metabolic and Bioenergetics Research, Houston Methodist Research Institute and Weill Cornell Medical College, Houston, Texas Houston Methodist Research Institute, Houston, Texas aagupte@houstonmethodist.org.
authors: Anisha A
authors: AA
authors: Gupte
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects / Q000379:methods*; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism; D010052:Ovariectomy / Q000379:methods* / Q000662:veterinary; D015430:Weight Gain
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D005947:Glucose
keywords: ER
  α; Energy balance; estrogen; mitochondria