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Fischer, K. ; Fenzl, A. ; Liu, D.* ; Dyar, K.A. ; Kleinert, M. ; Brielmeier, M. ; Clemmensen, C. ; Fedl, A. ; Finan, B. ; Gessner, A.* ; Jastroch, M. ; Huang, J.* ; Keipert, S. ; Klingenspor, M.* ; Brüning, J.C.* ; Kneilling, M.* ; Maier, F.C.* ; Othman, A.E.* ; Pichler, B.J.* ; Pramme-Steinwachs, I. ; Sachs, S. ; Scheideler, A. ; Thaiss, W.M.* ; Uhlenhaut, N.H. ; Ussar, S. ; Woods, S.C.* ; Zorn, J.* ; Stemmer, K. ; Collins, S.* ; Diaz-Meco, M.* ; Moscat, J.* ; Tschöp, M.H. ; Müller, T.D.

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.

Nat. Commun. 11:2306 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Brown Adipose-tissue; Transcription; Kinase; Fat; Resistance
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 11, Issue: 1, Pages: , Article Number: 2306 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status