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

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

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FISCHER, Katrin, Anna FENZL, Dianxin LIU, Kenneth A. DYAR, Maximilian KLEINERT, Markus BRIELMEIER, Christoffer CLEMMENSEN, Anna FEDL, Kerstin STEMMER, Timo D. MÜLLER, 2020. The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. In: Nature Communications. Nature Publishing Group. 11(1), 2306. eISSN 2041-1723. Available under: doi: 10.1038/s41467-020-16230-8

@article{Fischer2020-05-08scaff-52200, title={The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation}, year={2020}, doi={10.1038/s41467-020-16230-8}, number={1}, volume={11}, journal={Nature Communications}, author={Fischer, Katrin and Fenzl, Anna and Liu, Dianxin and Dyar, Kenneth A. and Kleinert, Maximilian and Brielmeier, Markus and Clemmensen, Christoffer and Fedl, Anna and Stemmer, Kerstin and Müller, Timo D.}, note={Article Number: 2306} }

Dyar, Kenneth A. Clemmensen, Christoffer Fischer, Katrin eng Stemmer, Kerstin Liu, Dianxin Fedl, Anna Clemmensen, Christoffer Brielmeier, Markus Dyar, Kenneth A. Kleinert, Maximilian Fedl, Anna Kleinert, Maximilian 2020-05-08 Stemmer, Kerstin Fenzl, Anna Brielmeier, Markus Müller, Timo D. Müller, Timo D. Liu, Dianxin Fenzl, Anna 2020-12-21T11:10:31Z Attribution 4.0 International 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. P62<sup>Δ69-251</sup> 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 p62<sup>Δ69-251</sup> mice, global p62<sup>-/-</sup> and Ucp1-Cre p62<sup>flx/flx</sup> 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. Fischer, Katrin 2020-12-21T11:10:31Z The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation

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