1. Academic Validation
  2. AMPKα1 regulates Idh2 transcription through H2B O-GlcNAcylation during brown adipogenesis

AMPKα1 regulates Idh2 transcription through H2B O-GlcNAcylation during brown adipogenesis

  • Acta Biochim Biophys Sin (Shanghai). 2021 Jan 12;53(1):112-118. doi: 10.1093/abbs/gmaa136.
Yuxin Cao 1 Xiangdong Liu 2 Junxing Zhao 1 Min Du 2
Affiliations

Affiliations

  • 1 Department of Animal Sciences and Veterinary Medicine, Shanxi Agricultural University, Taigu 030801, China.
  • 2 Department of Animal Sciences, Washington State University, Pullman, WA 99164, USA.
Abstract

AMP-activated protein kinase (AMPK) is indispensable for the development and maintenance of brown adipose tissue (BAT), and its activity is inhibited due to obesity. The isocitrate dehydrogenase 2 (IDH2) is a mitochondrial Enzyme responsible for the production of α-ketoglutarate, a key intermediate metabolite integrating multiple metabolic processes. We previously found that AMPKα1 ablation reduced cellular α-ketoglutarate concentration during brown adipocyte differentiation, but the effect of AMPKα1 on IDH2 expression remains undefined. In the present study, mouse C3H10T1/2 cells were transfected with Idh2-CRISPR/Cas9, and induced to brown adipogenesis. Our data suggested that brown adipogenesis was compromised due to IDH2 deficiency in vitro, which was accompanied by down-regulation of PR-domain containing 16. Importantly, the IDH2 content was reduced in brown stromal vascular cells (BSVs) separated from AMPKα1 knockout (KO) BAT, which was associated with lower contents of histone 2B (H2B) O-GlcNAcylation and monoubiquitination. Furthermore, both GlcNAcylated-H2B (S112) and ubiquityl-histone 2B (K120) contents in the IDH2 promoter were decreased in AMPKα1 KO BSVs. Meanwhile, ectopic O-linked N-acetylglucosamine transferase (OGT) expression was positively correlated with IDH2 expression, while OGT (T444A) mutation abolished the regulatory effect of AMPKα1 on IDH2. In vivo, reduced AMPKα1 activity and lower IDH2 abundance were observed in BAT of obese mice when compared with those in control mice. Taken together, our data demonstrated that IDH2 is necessary for brown adipogenesis and that AMPKα1 deficiency attenuates IDH2 expression, which might be by suppressing H2B O-GlcNAcylation modification.

Keywords

AMPKα1; IDH2; brown adipose tissue; epigenetics.

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