| First Author | Handgraaf S | Year | 2013 |
| Journal | Diabetes | Volume | 62 |
| Issue | 12 | Pages | 4098-108 |
| PubMed ID | 23903353 | Mgi Jnum | J:208933 |
| Mgi Id | MGI:5565408 | Doi | 10.2337/db13-0282 |
| Citation | Handgraaf S, et al. (2013) Prevention of obesity and insulin resistance by estrogens requires ERalpha activation function-2 (ERalphaAF-2), whereas ERalphaAF-1 is dispensable. Diabetes 62(12):4098-108 |
| abstractText | The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor alpha (ERalpha), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERalphaAF-1 (ERalphaAF-1 degrees ) or ERalphaAF-2 (ERalphaAF-2 degrees ), we determined their respective roles in the actions of estrogens on body composition and glucose homeostasis in response to either a normal diet or a high-fat diet (HFD). ERalphaAF-2 degrees males and females developed accelerated weight gain, massive adiposity, severe insulin resistance, and glucose intolerance--quite reminiscent of the phenotype observed in mice deleted for the entire ERalpha protein (ERalpha(-/-)). In striking contrast, ERalphaAF-1 degrees and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17beta-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERalphaAF-1 degrees ovariectomized mice, whereas these actions were totally abrogated in ERalphaAF-2 degrees and ERalpha(-/-) mice. Thus, whereas both AFs have been previously shown to contribute to endometrial and breast cancer cell proliferation, the protective effect of estrogens against obesity and insulin resistance depends on ERalphaAF-2 but not ERalphaAF-1, thereby delineating new options for selective modulation of ERalpha. |
