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Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable

Handgraaf, S., Riant, E., Fabre, A., Waget, A., Burcelin, R., Lière, P., Krust, A., Chambon, P., Arnal, J.F., Gourdy, P.

The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor α (ERα), a nuclear receptor that regulates gene transcription through two activation functions (AFs): AF-1 and AF-2. Using mouse models deleted electively for ERαAF-1 (ERαAF-1°) or ERαAF-2 (ERαAF-2°), 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). ERαAF-2° 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 ERα protein (ERα−/−). In striking contrast, ERαAF-1° and wild-type (wt) mice shared a similar metabolic phenotype. Accordingly, 17β-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against HFD-induced metabolic disturbances in wt and ERαAF-1° ovariectomized mice, whereas these actions were totally abrogated in ERαAF-2° and ERα−/− 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 ERαAF-2 but not ERαAF-1, thereby delineating new options for selective modulation of ERα.

Citation

Handgraaf, S., Riant, E., Fabre, A., Waget, A., Burcelin, R., Lière, P., Krust, A., Chambon, P., Arnal, J.F., Gourdy, P. "Prevention of Obesity and Insulin Resistance by Estrogens Requires ERα Activation Function-2 (ERαAF-2), Whereas ERαAF-1 Is Dispensable" Diabetes (2013): 4,098–108