title: Pharmacologic activation of estrogen receptor β 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.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Suriyan
authors.initials: S
authors.lastname: Ponnusamy
authors.affiliation: Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Quynh T
authors.initials: QT
authors.lastname: Tran
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Innocence
authors.initials: I
authors.lastname: Harvey
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Smallwood
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Thirumagal
authors.initials: T
authors.lastname: Thiyagarajan
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Souvik
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Molecular Informatics Core, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Johnson
authors.affiliation: Preclinical Research and Development, GTx, Incorporated, Memphis, Tennessee, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.affiliation: Department of Comparative Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Sullivan
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.|Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Bridges
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA; rnaraya4@uthsc.edu.|West Cancer Center, Memphis, Tennessee, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000502:physiology; D000818:Animals; D015415:Biomarkers; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000502:physiology*; D009765:Obesity / Q000097:blood / Q000378:metabolism
chemical_list: D015415:Biomarkers; D047629:Estrogen Receptor beta; D007546:Isoquinolines; C585485:beta-LGND2
keywords: exercise mimetic; metabolic diseases; mitochondria; obesity; oxygen consumption