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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 Δ69-251  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 p62 Δ69-251  mice, global p62 −/−  and Ucp1-Cre p62 flx/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.

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