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

ABSTRACT: During ?-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-1?. 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-1? promoter. P62^?69-251 mice show reduced expression of Ucp1 and Pgc-1? with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1? expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62^?69-251 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.

SUBMITTER: Fischer K

PROVIDER: S-EPMC7211001 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Fischer Katrin K Fenzl Anna A Liu Dianxin D Dyar Kenneth A KA Kleinert Maximilian M Brielmeier Markus M Clemmensen Christoffer C Fedl Anna A Finan Brian B Gessner Andre A Jastroch Martin M Huang Jianfeng J Keipert Susanne S Klingenspor Martin M Brüning Jens C JC Kneilling Manfred M Maier Florian C FC Othman Ahmed E AE Pichler Bernd J BJ Pramme-Steinwachs Ines I Sachs Stephan S Scheideler Angelika A Thaiss Wolfgang M WM Uhlenhaut Henriette H Ussar Siegfried S Woods Stephen C SC Zorn Julia J Stemmer Kerstin K Collins Sheila S Diaz-Meco Maria M Moscat Jorge J Tschöp Matthias H MH Müller Timo D TD

Nature communications 20200508 1

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<sup>Δ69-251</sup> mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. ...[more]

PMID: 32385399

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Project description:ObjectiveBrown adipose tissue (BAT) is specialized in thermogenesis. The conversion of energy into heat in brown adipocytes proceeds via stimulation of ?-adrenergic receptor (?AR)-dependent signaling and activation of mitochondrial uncoupling protein 1 (UCP1). We have previously demonstrated a functional role for pannexin-1 (Panx1) channels in white adipose tissue; however, it is not known whether Panx1 channels play a role in the regulation of brown adipocyte function. Here, we tested the hypothesis that Panx1 channels are involved in brown adipocyte activation and thermogenesis.MethodsIn an immortalized brown pre-adipocytes cell line, Panx1 currents were measured using patch-clamp electrophysiology. Flow cytometry was used for assessment of dye uptake and luminescence assays for adenosine triphosphate (ATP) release, and cellular temperature measurement was performed using a ratiometric fluorescence thermometer. We used RNA interference and expression plasmids to manipulate expression of wild-type and mutant Panx1. We used previously described adipocyte-specific Panx1 knockout mice (Panx1Adip-/-) and generated brown adipocyte-specific Panx1 knockout mice (Panx1BAT-/-) to study pharmacological or cold-induced thermogenesis. Glucose uptake into brown adipose tissue was quantified by positron emission tomography (PET) analysis of 18F-fluorodeoxyglucose (18F-FDG) content. BAT temperature was measured using an implantable telemetric temperature probe.ResultsIn brown adipocytes, Panx1 channel activity was induced either by apoptosis-dependent caspase activation or by ?3AR stimulation via a novel mechanism that involves G?? subunit binding to Panx1. Inactivation of Panx1 channels in cultured brown adipocytes resulted in inhibition of ?3AR-induced lipolysis, UCP-1 expression, and cellular thermogenesis. In mice, adiponectin-Cre-dependent genetic deletion of Panx1 in all adipose tissue depots resulted in defective ?3AR agonist- or cold-induced thermogenesis in BAT and suppressed beigeing of white adipose tissue. UCP1-Cre-dependent Panx1 deletion specifically in brown adipocytes reduced the capacity for adaptive thermogenesis without affecting beigeing of white adipose tissue and aggravated diet-induced obesity and insulin resistance.ConclusionsThese data demonstrate that G??-dependent Panx1 channel activation is involved in ?3AR-induced thermogenic regulation in brown adipocytes. Identification of Panx1 channels in BAT as novel thermo-regulatory elements downstream of ?3AR activation may have therapeutic implications.

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

Publications

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

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