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Pharmacologic activation of estrogen receptor ? increases mitochondrial function, energy expenditure, and brown adipose tissue.


ABSTRACT: Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor ? (ER-?) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-? and its ligands. Estrogen receptor ? (ER-?) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-?-selective ligand increased markers of tricarboxylic acid-dependent and -independent energy biogenesis and oxygen consumption in mice without a concomitant increase in physical activity or food consumption, all culminating in significantly reduced weight gain and adiposity. The antiobesity effects of ER-? ligand were not observed in ER-?-knockout mice. Serum metabolite profiles of adult lean and juvenile mice were comparable, while that of adult obese mice was distinct, indicating a possible impact of obesity on age-dependent metabolism. This phenotype was partially reversed by ER-?-selective ligand. These data highlight a new role for ER-? in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.-Ponnusamy, S., Tran, Q. T., Harvey, I., Smallwood, H. S., Thiyagarajan, T., Banerjee, S., Johnson, D. L., Dalton, J. T., Sullivan, R. D., Miller, D. D., Bridges, D., Narayanan, R. Pharmacologic activation of estrogen receptor ? increases mitochondrial function, energy expenditure, and brown adipose tissue.

SUBMITTER: Ponnusamy S 

PROVIDER: S-EPMC5161516 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Pharmacologic activation of estrogen receptor β increases mitochondrial function, energy expenditure, and brown adipose tissue.

Ponnusamy Suriyan S   Tran Quynh T QT   Harvey Innocence I   Smallwood Heather S HS   Thiyagarajan Thirumagal T   Banerjee Souvik S   Johnson Daniel L DL   Dalton James T JT   Sullivan Ryan D RD   Miller Duane D DD   Bridges Dave D   Narayanan Ramesh R  

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20161012 1


Most satiety-inducing obesity therapeutics, despite modest efficacy, have safety concerns that underscore the need for effective peripherally acting drugs. An attractive therapeutic approach for obesity is to optimize/maximize energy expenditure by increasing energy-utilizing thermogenic brown adipose tissue. We used in vivo and in vitro models to determine the role of estrogen receptor β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechan  ...[more]

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