Research ArticleMetabolism

Estrogen receptor α controls metabolism in white and brown adipocytes by regulating Polg1 and mitochondrial remodeling

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Science Translational Medicine  05 Aug 2020:
Vol. 12, Issue 555, eaax8096
DOI: 10.1126/scitranslmed.aax8096

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Estrogen receptor energetics

The estrogen receptor α (ERα; encoded by ESR1) is implicated in aging-related obesity. Zhou et al. now provide evidence that ERα affects metabolism by controlling mitochondrial dynamics and function in both white and brown adipose tissue. Expression of ESR1 in adipose tissue associated with reduced visceral adiposity and increased insulin sensitivity in two independent human cohorts and a panel of mice. Follow-up experiments in mice indicated that Esr1 deletion in white adipose tissue promoted parkin-driven mitophagy, whereas Esr1 deletion in brown adipose tissue reduced thermogenesis. Mechanistically, the authors tied these metabolic responses to direct ERα-driven control of a mitochondrial DNA polymerase subunit in both types of fat.

Abstract

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 ESR1/Esr1 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 Esr1 from white and brown adipocytes in mice. In white adipose tissue, Esr1 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, Esr1 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 Esr1 deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit Polg1. We identified Polg1 as an ERα target gene by showing that ERα binds the Polg1 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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