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

Nat Commun. 2020 May 8;11(1):2306. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Activating Transcription Factor 2
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • p38 Mitogen-Activated Protein Kinases