Fischer, Katrin, Fenzl, Anna, Liu, Dianxin, Dyar, Kenneth A., Kleinert, Maximilian ORCID: 0000-0002-8069-9055, Brielmeier, Markus ORCID: 0000-0002-8715-869X, Clemmensen, Christoffer ORCID: 0000-0003-2456-9667, Fedl, Anna, Finan, Brian, Gessner, Andre, Jastroch, Martin, Huang, Jianfeng, Keipert, Susanne, Klingenspor, Martin, Bruening, Jens C., Kneilling, Manfred, Maier, Florian C., Othman, Ahmed E., Pichler, Bernd J., Pramme-Steinwachs, Ines, Sachs, Stephan, Scheideler, Angelika, Thaiss, Wolfgang M., Uhlenhaut, Henriette ORCID: 0000-0002-4220-4779, Ussar, Siegfried ORCID: 0000-0001-7575-0920, Woods, Stephen C., Zorn, Julia, Stemmer, Kerstin, Collins, Sheila, Diaz-Meco, Maria, Moscat, Jorge, Tschoep, Matthias H. and Mueller, Timo D. (2020). The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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Abstract

During beta -adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1 alpha. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1 alpha promoter. P62(Delta 69-251) mice show reduced expression of Ucp1 and Pgc-1 alpha with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1 alpha expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62(Delta 69-251) mice, global p62(-/-) and Ucp1-Cre p62(flx/flx) mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding. Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1 alpha. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1 alpha induction.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fischer, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fenzl, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, DianxinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dyar, Kenneth A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kleinert, MaximilianUNSPECIFIEDorcid.org/0000-0002-8069-9055UNSPECIFIED
Brielmeier, MarkusUNSPECIFIEDorcid.org/0000-0002-8715-869XUNSPECIFIED
Clemmensen, ChristofferUNSPECIFIEDorcid.org/0000-0003-2456-9667UNSPECIFIED
Fedl, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Finan, BrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gessner, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jastroch, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, JianfengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keipert, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klingenspor, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kneilling, ManfredUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maier, Florian C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Othman, Ahmed E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichler, Bernd J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pramme-Steinwachs, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sachs, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheideler, AngelikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thaiss, Wolfgang M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlenhaut, HenrietteUNSPECIFIEDorcid.org/0000-0002-4220-4779UNSPECIFIED
Ussar, SiegfriedUNSPECIFIEDorcid.org/0000-0001-7575-0920UNSPECIFIED
Woods, Stephen C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zorn, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stemmer, KerstinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Collins, SheilaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diaz-Meco, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moscat, JorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tschoep, Matthias H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Timo D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-334161
DOI: 10.1038/s41467-020-16230-8
Journal or Publication Title: Nat. Commun.
Volume: 11
Number: 1
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BROWN ADIPOSE-TISSUE; TRANSCRIPTION; KINASE; FAT; RESISTANCEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/33416

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