Estrogen receptor inhibition enhances cold-induced adipocyte beiging and glucose tolerance

Kfir Lapid, Ajin Lim, Eric D. Berglund, Yue Lu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Low estrogen states, exemplified by postmenopausal women, are associated with increased adiposity and metabolic dysfunction. We recently reported a paradox, in which a conditional estrogen receptor-alpha (ERα) mutant mouse shows a hyper-metabolic phenotype with enhanced brown/beige cell formation (“browning/beiging”). Hypothesis: These observations led us to consider that although systemic deficiency of estrogen or ERα in mice results in obesity and glucose intolerance at room temperature, cold exposure might induce enhanced browning/beiging and improve glucose metabolism. Methods and results: Remarkably, studying cold-exposure in mouse models of inhibited estrogen signaling - ERαKO mice, ovariectomy, and treatment with the ERα antagonist Fulvestrant - supported this notion. ERα/estrogen-deficient mice demonstrated enhanced cold induced beiging, reduced adiposity and improved glucose tolerance.Fulvestrant was also effective in diet-induced obesity settings. Mechanistically, ERα inhibition sensitized cell-autonomous beige cell differentiation and stimulation, including β3-adrenoreceptor-dependent adipocyte beiging. Conclusion: Taken together, our findings highlight a therapeutic potential for obese/diabetic postmenopausal patients; cold exposure is therefore predicted to metabolically benefit those patients.

Original languageEnglish (US)
Pages (from-to)1419-1436
Number of pages18
JournalDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Volume12
DOIs
StatePublished - 2019

Keywords

  • Adipose tissue
  • Brown fat
  • Diabetes
  • Obesity
  • Post-menopause

ASJC Scopus subject areas

  • Internal Medicine
  • Pharmacology

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