Title | The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | 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 |
Journal | Nat Commun |
Volume | 11 |
Issue | 1 |
Pagination | 2306 |
Date Published | 2020 05 08 |
ISSN | 2041-1723 |
Keywords | 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 |
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. 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. |
DOI | 10.1038/s41467-020-16230-8 |
Alternate Journal | Nat Commun |
PubMed ID | 32385399 |
PubMed Central ID | PMC7211001 |
Grant List | R01 CA211794 / CA / NCI NIH HHS / United States P30 DK058404 / DK / NIDDK NIH HHS / United States R01 CA218254 / CA / NCI NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States R01 CA207177 / CA / NCI NIH HHS / United States R01 DK108743 / DK / NIDDK NIH HHS / United States |
Related Faculty:
Jorge Moscat, Ph.D.