The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.
Katrin FischerAnna FenzlDianxin LiuKenneth A DyarMaximilian KleinertMarkus BrielmeierChristoffer ClemmensenAnna FedlBrian FinanAndre GessnerMartin JastrochJianfeng HuangSusanne KeipertMartin KlingensporJens C BrüningManfred KneillingFlorian C MaierAhmed E OthmanBernd J PichlerInes Pramme-SteinwachsStephan SachsAngelika ScheidelerWolfgang M ThaissNina Henriette UhlenhautSiegfried UssarStephen C WoodsJulia ZornKerstin StemmerSheila CollinsMaria T Diaz-MecoJorge MoscatMatthias H TschöpTimo Dirk MüllerPublished in: Nature communications (2020)
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.
Keyphrases
- transcription factor
- dna binding
- adipose tissue
- high fat diet induced
- endoplasmic reticulum stress
- skeletal muscle
- poor prognosis
- binding protein
- insulin resistance
- genome wide identification
- metabolic syndrome
- high fat diet
- oxidative stress
- weight loss
- gene expression
- body mass index
- big data
- wild type
- protein protein
- small molecule