Estrogen receptor α controls metabolism in white and brown adipocytes by regulating and mitochondrial remodeling.

Zhou, Z., et al. “Estrogen Receptor Α Controls Metabolism In White And Brown Adipocytes By Regulating And Mitochondrial Remodeling.”. Science Translational Medicine.
Author Zhenqi Zhou, Timothy M Moore, Brian G Drew, Vicent Ribas, Jonathan Wanagat, Mete Civelek, Mayuko Segawa, Dane M Wolf, Frode Norheim, Marcus M Seldin, Alexander R Strumwasser, Kate A Whitney, Ellen Lester, Britany R Reddish, Laurent Vergnes, Karen Reue, Prashant Rajbhandari, Peter Tontonoz, Jason Lee, Sushil K Mahata, Sylvia C Hewitt, Orian Shirihai, Craig Gastonbury, Kerrin S Small, Markku Laakso, Jorgen Jensen, Sindre Lee, Christian A Drevon, Kenneth S Korach, Aldons J Lusis, Andrea L Hevener

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted from white and brown adipocytes in mice. In white adipose tissue, controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit We identified as an ERα target gene by showing that ERα binds the promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.

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Science translational medicine
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Sci Transl Med