Pharmacologic activation of estrogen receptor α 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 β (ER-β) and its ligands on adipose biology. RNA sequencing and metabolomics were used to determine the mechanism of action of ER-β and its ligands. Estrogen receptor β (ER-β) and its selective ligand reprogrammed preadipocytes and precursor stem cells into brown adipose tissue and increased mitochondrial respiration. An ER-β-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-β ligand were not observed in ER-β-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-β-selective ligand. These data highlight a new role for ER-β 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 β increases mitochondrial function, energy expenditure, and brown adipose tissue.

The role of estrogens in the adipose tissue milieu

“…In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency. In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency.…”

“…While the mechanisms by which signaling through ERβ may have antiobesity effects are not clear, new evidence implicates ERβ as a primary mediator of 17β-E2's protective metabolic effects regarding adipose tissue mitochondrial activity. In a recent series of preclinical studies, [151][152][153] it was demonstrated that ERβ-specific ligands have powerful antiobesity effects and increase energy expenditure and mitochondrial activity in adipose tissues, including in the setting of ovarian hormone deficiency. 150 A major caveat is that the majority of these studies investigating isotype-specific effects of ER signaling have been done in rodent models, not humans.…”

An estrogen receptor β-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors

“…Body weight and body composition data from the experiments described in the manuscript were presented in our previous publication. 20 CON diet-fed mice consumed 173AE 12 g/ seven animals/week, while the HFD-fed vehicle-treated and b-LGND2-treated mice consumed 105 AE 17 g/seven mice/week and 111 AE 8 g/seven mice/week, respectively. At the end of 10 weeks, the animals were sacrificed and blood and tissues were collected for gene expression, histology, and metabolomics.…”

“…Earlier studies from our group showed that one of the ER-b-selective agonists belonging to the isoquinolinone scaffold, b-LGND2, prevented high fat diet (HFD) induced body weight and adipose tissue gain, without affecting food consumption by acting peripherally by converting white adipose tissue (WAT) to brown adipose tissue (BAT). 19,20 This conversion of WAT to BAT by b-LGND2 resulted in an increase in thermogenesis and oxygen consumption, all culminating in weight loss. b-LGND2 was more effective than some of the commercial drugs used as comparator.…”

“…b-LGND2 was more effective than some of the commercial drugs used as comparator. 20 Due to the favorable changes promoted by b-LGND2 on body weight and composition, we expected b-LGND2 to effectively reduce lipid accumulation in the liver of preclinical species. To test this hypothesis, we evaluated b-LGND2 in two preclinical models of fatty liver disease 21,22 and performed studies to understand the underlying mechanisms of action.…”