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

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 (ER) mutant mouse shows a hyper-metabolic phenotype with enhanced brown/beige cell formation (\"browning/beiging\"). These observations led us to consider that although systemic deficiency of estrogen or ER in mice results in obesity and glucose intolerance at room-temperature, cold-exposure might induce enhanced browning/beiging and improve glucose metabolism. Remarkably, studying cold-exposure in mouse models of inhibited estrogen signaling - ERKO mice, ovariectomy, and treatment with the ER antagonist Fulvestrant - supported this notion. ER/estrogen deficient mice demonstrated enhanced cold-induced beiging, reduced adiposity and increased glucose sensitivity. Fulvestrant was also effective in diet-induced obesity settings. Mechanistically, ER inhibition sensitized cell-autonomous beige cell differentiation and stimulation, including {beta}3-adrenoreceptor-dependent adipocyte beiging. Taken together, our findings highlight a therapeutic potential for obese/diabetic postmenopausal patients.