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

Katrin Fischer,Angelika Scheideler,Jens C Brüning,Martin Jastroch,Jorge Moscat,Bernd J Pichler,Julia Zorn,M Tschöp ,Anna Fenzl,Sheila Collins,Martin Klingenspor,Jianfeng Huang,Christoffer Clemmensen,Dianxin Liu,Brian Finan,N Henriette Uhlenhaut ,Siegfried Ussar,Kerstin Stemmer,Maximilian Kleinert,Wolfgang Thaiss ,Manfred Kneilling,Stephen C Woods,Stephan Sachs,Ines Pramme-Steinwachs,Kenneth A Dyar,Florian Maier ,Markus Brielmeier,Susanne Keipert,Marı́a T Diaz-Meco ,Anna S Fedl ,André Gessner ,Ahmed E Othman,Timo Müller

doi:10.1038/s41467-020-16230-8

Abstract

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.

Highlights

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which translocates to the nucleus to activate the expression of Ucp[1] and Pgc-1α
In a series of in vitro and in vivo experiments using p62Δ69-251 mice, global p62-deficient mice (p62−/−) and uncoupling protein 1 (Ucp1)-Cre p62flx/flx mice, we demonstrate that p62 is a key signaling node of the UCP1 pathway. p62 directly binds to ATF2 to orchestrate its genomic binding to and activation of the Ucp[1] enhancer and Pgc-1α promoter
Consistent with this, we see no difference in protein levels of phosphorylated protein kinase C in the liver (Supplementary Fig. 1b) and of p-ERK1/2 in white adipose tissue (WAT) of p62Δ69-251 mice (Supplementary Fig. 1c, d)

Summary

Introduction

During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which translocates to the nucleus to activate the expression of Ucp[1] and Pgc-1α. Modulation of Ucp[1] 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. Our data demonstrate that mice that lack the amino acids (aa) 69–251 of the p62 protein (p62Δ69-251 mice) have normal protein levels of p-ERK1/2 in WAT and show no changes in adipogenesis or adipocyte differentiation These mice develop a severe obese phenotype that is accompanied by impaired energy expenditure and dysfunctional BAT. As demonstrated in p62Δ69251 mice, global p62−/− mice and Ucp1-Cre p62flx/flx mice, lack of p62 action leads to failure of ATF2 to activate its nuclear targets Ucp[1] and Pgc1α and results in impaired BAT function and increased body weight. Our data establish p62 as a key regulator of adaptive thermogenesis in that it regulates the UCP1 pathway via modulation of ATF2 genomic target activation

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