title: Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue.
abstract: The Rar-related orphan receptor-α (Rorα) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rorα-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Rorα-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Pparα, Errα, Dio2, Acot11/Bfit, Cpt1β, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesity-resistant phenotype in Rorα-deficient mice.
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Patrick
authors.initials: P
authors.lastname: Lau
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Zewen K
authors.initials: ZK
authors.lastname: Tuong
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Fitzsimmons
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Joel M
authors.initials: JM
authors.lastname: Goode
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, Queensland, Australia; and.
authors.forename: Gethin P
authors.initials: GP
authors.lastname: Thomas
authors.affiliation: Centre for Advanced Imaging, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Cowin
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pearen
authors.affiliation: Centre for Advanced Imaging, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Karine
authors.initials: K
authors.lastname: Mardon
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stow
authors.affiliation: Obesity Research Centre, Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia; g.muscat@imb.uq.edu.au.
authors.forename: George E O
authors.initials: GE
authors.lastname: Muscat
mesh_terms: D015502:Absorptiometry, Photon; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D001823:Body Composition / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007473:Ion Channels / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D024101:Mitochondrial Proteins / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D022722:Thermogenesis / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D004268:DNA-Binding Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D012313:RNA; D011495:Histone-Lysine N-Methyltransferase
keywords: adipose tissue; adiposity; obesity; retinoic acid receptor-related orphan receptor-α; uncoupling protein-1