title: p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α.
abstract: The tumor suppressor p53 (TRP53 in mice) is known for its involvement in carcinogenesis, but work during recent years has underscored the importance of p53 in the regulation of whole body metabolism. A general notion is that p53 is necessary for efficient oxidative metabolism. The importance of UCP1-dependent uncoupled respiration and increased oxidation of glucose and fatty acids in brown or brown-like adipocytes, termed brite or beige, in relation to energy balance and homeostasis has been highlighted recently. UCP1-dependent uncoupled respiration in classic interscapular brown adipose tissue is central to cold-induced thermogenesis, whereas brite/beige adipocytes are of special importance in relation to diet-induced thermogenesis, where the importance of UCP1 is only clearly manifested in mice kept at thermoneutrality. We challenged wild-type and TRP53-deficient mice by high-fat feeding under thermoneutral conditions. Interestingly, mice lacking TRP53 gained less weight compared with their wild-type counterparts. This was related to an increased expression of Ucp1 and other PPARGC1a and PPARGC1b target genes but not Ppargc1a or Ppargc1b in inguinal white adipose tissue of mice lacking TRP53. We show that TRP53, independently of its ability to bind DNA, inhibits the activity of PPARGC1a and PPARGC1b. Collectively, our data show that TRP53 has the ability to regulate the thermogenic capacity of adipocytes through modulation of PPARGC1 activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark; Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Philip
authors.initials: P
authors.lastname: Hallenborg
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark; National Institute of Nutrition and Seafood Research, Bergen, Norway; and.
authors.forename: Even
authors.initials: E
authors.lastname: Fjære
authors.affiliation: National Institute of Nutrition and Seafood Research, Bergen, Norway; and.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Liaset
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Rasmus Koefoed
authors.initials: RK
authors.lastname: Petersen
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity Università Politecnica della Marche, Ancona, Italy.
authors.forename: Incoronata
authors.initials: I
authors.lastname: Murano
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Si Brask
authors.initials: SB
authors.lastname: Sonne
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Mathias
authors.initials: M
authors.lastname: Falkerslev
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Sally
authors.initials: S
authors.lastname: Winther
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Benjamin Anderschou Holbech
authors.initials: BA
authors.lastname: Jensen
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark;
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Hansen
authors.affiliation: Department of Experimental and Clinical Medicine, Center of Obesity Università Politecnica della Marche, Ancona, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;
authors.forename: Blagoy
authors.initials: B
authors.lastname: Blagoev
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark; National Institute of Nutrition and Seafood Research, Bergen, Norway; and.
authors.forename: Lise
authors.identifier: http://orcid.org/0000-0003-4468-1947
authors.initials: L
authors.lastname: Madsen
authors.affiliation: Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark; kk@bio.ku.dk.
authors.forename: Karsten
authors.initials: K
authors.lastname: Kristiansen
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D022722:Thermogenesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000071256:Uncoupling Protein 1; D015430:Weight Gain / Q000502:physiology
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1
keywords: peroxisome proliferator-activated receptor-γ