title: Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice.
abstract: Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine whether impaired estrogen action in female C57Bl6 mice, produced by whole body Esr1 ablation, could recapitulate aspects of this syndrome, including inflammation, insulin resistance, and obesity. Indeed, we found that global knockout (KO) of the estrogen receptor (ER)alpha leads to reduced oxygen uptake and caloric expenditure compared with wild-type (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated, whereas adiponectin levels were reduced in normal chow-fed KO. Furthermore, ERalpha-KO mice exhibited impaired glucose tolerance and marked skeletal muscle insulin resistance that was accompanied by the accumulation of bioactive lipid intermediates, inflammation, and diminished PPARalpha, PPARdelta, and UCP2 transcript levels. Although the relative glucose intolerance and insulin resistance phenotype in KO mice became more severe with high-fat feeding, WT mice were refractory to these dietary-induced effects, and this protection coincided with a marked increase in circulating adiponectin and heat shock protein 72 levels in muscle, liver, and fat. These data indicate that ERalpha is critical for the maintenance of whole body insulin action and protection against tissue inflammation during both normal chow and high-fat feeding.
authors.affiliation: David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, University of California Los Angeles, Los Angeles, California 90095-7073, USA.
authors.forename: Vicent
authors.initials: V
authors.lastname: Ribas
authors.forename: M T Audrey
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Darren C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: Anh-Khoi
authors.initials: AK
authors.lastname: Nguyen
authors.forename: Simon W
authors.initials: SW
authors.lastname: Beaven
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
mesh_terms: D050156:Adipogenesis / Q000502:physiology; D052242:Adiponectin / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology / Q000502:physiology*; D024821:Metabolic Syndrome / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009765:Obesity / Q000150:complications / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D010084:Oxidation-Reduction
chemical_list: D052242:Adiponectin; D004041:Dietary Fats; D047628:Estrogen Receptor alpha; D005227:Fatty Acids; D050884:HSP72 Heat-Shock Proteins