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

Abstract

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"). 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. Remarkably, studying cold-exposure in mouse models of inhibited estrogen signaling -ERαKO mice, ovariectomy, and treatment with the ERα antagonist Fulvestrantsupported this notion. ERα/estrogen deficient mice demonstrated enhanced cold-induced beiging, reduced adiposity and increased glucose sensitivity. 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. Taken together, our findings highlight a therapeutic potential for obese/diabetic postmenopausal patients.

Estrogen Receptor Beta Mediates the Dipsogenic Effect of Estradiol in Ovariectomized Female Rats

“…For decades, thermogenic, anorexigenic, and anti-dipsogenic effects of estradiol were reported and characterized in female laboratory rodents [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In 2019, it was reported that when female mice were housed in chronic cold stress conditions, estradiol inhibited thermogenic browning of white adipose tissue [21]. The following year, anorexigenic effect of estradiol was observed in female mice during rebound feeding [22].…”