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

Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD
Nat Commun. 2020 11 (1): 2306

PMID: 32385399 · PMCID: PMC7211001 · DOI:10.1038/s41467-020-16230-8

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 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 mice, global p62 and Ucp1-Cre p62 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.

MeSH Terms (18)

Activating Transcription Factor 2 Adipogenesis Adipose Tissue, Brown Adipose Tissue, White Animals Cell Nucleus Magnetic Resonance Imaging Male Mice Mice, Inbred C57BL Mice, Knockout Obesity p38 Mitogen-Activated Protein Kinases Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Positron Emission Tomography Computed Tomography Protein Binding Sequestosome-1 Protein Uncoupling Protein 1

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