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

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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