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

Suriyan Ponnusamy, Quynh Tran, Innocence Harvey, Heather Smallwood, Thirumagal Thiyagarajan, Souvik Banerjee, Daniel Johnson, James Dalton, Ryan Sullivan, Duane Miller, and Ramesh Narayanan

FASEB Journal 2017. 31: 266-281.


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 beta (ER-beta) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-beta and its ligands. Estrogen receptor beta (ER-beta) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-beta-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-beta ligand were not observed in ER-beta 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-beta-selective ligand. These data highlight a new role for ER-beta in adipose biology and its potential to be a safer alternative peripheral therapeutic target for obesity.


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