Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice

Vicent Ribas, M T Audrey Nguyen, Darren C Henstridge, Anh -Khoi Nguyen, Simon W Beaven, Matthew James Watt, Andrea L Hevener

Research output: Contribution to journalArticleResearchpeer-review

195 Citations (Scopus)

Abstract

Impaired estrogen action is associated with the metabolic syndrome in humans. We sought to determine if 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 find that global knockout (KO) of the estrogen receptor (ER)alpha leads to reduced oxygen uptake and caloric expenditure compared to wildtype (WT) mice. In addition, fasting insulin, leptin, and PAI-1 levels were markedly elevated while 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. While 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 (HSP)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.
Original languageEnglish
Pages (from-to)E304 - E319
Number of pages16
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume298
Issue number2
DOIs
Publication statusPublished - 2010

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