Prevention of obesity and insulin resistance by estrogens requires ERα activation function-2 (ERαAF-2), whereas ERαAF-1 is dispensable

S Handgraaf, E Riant, A Fabre, A Waget, R Burcelin… - Diabetes, 2013 - Am Diabetes Assoc
S Handgraaf, E Riant, A Fabre, A Waget, R Burcelin, P Lière, A Krust, P Chambon, JF Arnal…
Diabetes, 2013Am Diabetes Assoc
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 …
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.
Am Diabetes Assoc