295-OR: Estrogen Receptor a Controls Energy Homeostasis in White and Brown Adipose Tissue by Regulating Polg1 Expression and Mitochondrial Remodeling

Abstract

Obesity is heightened during aging. Although the role of the estrogen receptor (ER)α to prevent obesity is supported by our previous work, ERα actions in adipocytes remain inadequately understood. Gene expression analysis from UKTwins Study, METSIM Study, and the study of the UCLA Hybrid Mouse Diversity Panel show that ESR1/Esr1 is inversely associated with adiposity and markers of metabolic health in both humans and mice. To determine the mechanistic role(s) of ERα in fat, we generated 2 adipose tissue-specific knockout mouse lines by selectively deleting Esr1 from white and brown adipose tissue (FERKO and ERαKOBAT, respectively). In white adipose tissue, Esr1 controls oxidative metabolism by reducing the E3 ubiquitin ligase Parkin-mediated mitochondrial degradation. Indeed, we report that adipose tissue-selective Parkin knockout mice have reduced body fat and elevated adipocyte mtDNA content. In brown adipose tissue, Esr1 is a requisite for mitochondrial remodeling and cold-induced thermogenesis. Although the role of mitochondrial metabolism differs between white and brown fat, the unique mitochondrial phenotypes observed in white and brown Esr1-deficient adipocytes, appear to be the consequence of reduced expression of the mtDNA polymerase, Polg1. We provide direct evidence that ERα binds the Polg1 promoter to control its expression, and that selective phenotypes of ERα deficiency are recapitulated by Polg1 deletion. Collectively our findings show that ERα has strong heritability in adipose tissue and support strategies targeting cell-specific actions of ERα to combat diseases associated with metabolic dysfunction. Disclosure Z. Zhou: None. A.L. Hevener: None. Funding National Institutes of Health (U54DK120342)