Selective Activation of Estrogen Receptor α Activation Function-1 Is Sufficient to Prevent Obesity, Steatosis, and Insulin Resistance in Mouse

The American Journal of Pathology
Maeva GuillaumePierre Gourdy

Abstract

Estrogen receptor α (ERα) regulates gene transcription through two activation functions (ERα-AF1 and ERα-AF2). We recently found that the protection conferred by 17β-estradiol against obesity and insulin resistance requires ERα-AF2 but not ERα-AF1. However, the interplay between the two ERα-AFs is poorly understood in vivo and the metabolic influence of a specific ERα-AF1 action remains to be explored. To this end, wild-type, ERα-deficient, or ERα-AF1-deficient ovariectomized female mice were fed a high-fat diet and concomitantly administered with vehicle or tamoxifen, a selective ER modulator that acts as a ERα-AF1 agonist/ERα-AF2 antagonist. In ovariectomized wild-type mice, tamoxifen significantly reduced food intake and totally prevented adiposity, insulin resistance, and steatosis. These effects were abolished in ERα-deficient and ERα-AF1-deficient mice, revealing the specific role of ERα-AF1 activation. Finally, hepatic gene expression changes elicited by tamoxifen in wild-type mice were abrogated in ERα-AF1-deficient mice. The combination of pharmacologic and transgenic approaches thus indicates that selective ERα-AF1 activation by tamoxifen is sufficient to elicit metabolic protection, contrasting with the specific requ...Continue Reading

Citations

Jan 10, 2019·Médecine sciences : M/S·Marie-Cécile ValéraJean-François Arnal
Jun 11, 2020·Journal of Developmental Origins of Health and Disease·Iala Milene BertassoPatricia Cristina Lisboa
Feb 6, 2019·Experimental Biology and Medicine·Suresh Mishra, Bl Grégoire Nyomba
Oct 6, 2020·Circulation Research·Rana ZahreddineCoralie Fontaine
Feb 1, 2020·Molecular and Cellular Endocrinology·Coralie FontaineJean-François Arnal
Oct 7, 2021·Diabetic Medicine : a Journal of the British Diabetic Association·Lydia F Daniels GatwardAileen J F King

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