TY - JOUR
T1 - The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation
AU - Fischer, Katrin
AU - Fenzl, Anna
AU - Liu, Dianxin
AU - Dyar, Kenneth A.
AU - Kleinert, Maximilian
AU - Brielmeier, Markus
AU - Clemmensen, Christoffer
AU - Fedl, Anna
AU - Finan, Brian
AU - Gessner, Andre
AU - Jastroch, Martin
AU - Huang, Jianfeng
AU - Keipert, Susanne
AU - Klingenspor, Martin
AU - Brüning, Jens C.
AU - Kneilling, Manfred
AU - Maier, Florian C.
AU - Othman, Ahmed E.
AU - Pichler, Bernd J.
AU - Pramme-Steinwachs, Ines
AU - Sachs, Stephan
AU - Scheideler, Angelika
AU - Thaiss, Wolfgang M.
AU - Uhlenhaut, Henriette
AU - Ussar, Siegfried
AU - Woods, Stephen C.
AU - Zorn, Julia
AU - Stemmer, Kerstin
AU - Collins, Sheila
AU - Diaz-Meco, Maria
AU - Moscat, Jorge
AU - Tschöp, Matthias H.
AU - Müller, Timo D.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - During β-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-1α. 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-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/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.
AB - During β-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-1α. 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-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62−/− and Ucp1-Cre p62flx/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.
UR - http://www.scopus.com/inward/record.url?scp=85084720487&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-16230-8
DO - 10.1038/s41467-020-16230-8
M3 - Article
C2 - 32385399
AN - SCOPUS:85084720487
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2306
ER -