Journal article
AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis
Cell metabolism, Vol.24(4), pp.542-554
10/11/2016
Handle:
https://hdl.handle.net/2376/113154
PMCID: PMC5061633
PMID: 27641099
Abstract
Promoting brown adipose tissue (BAT) development is an attractive strategy for the treatment of obesity, as activated BAT dissipates energy through thermogenesis; however, the mechanisms controlling BAT formation are not fully understood. We hypothesized that as a master regulator of energy metabolism, AMP-activated protein kinase (AMPK) may play a direct role in the process and found that AMPKα1 (PRKAA1) ablation reduced
Prdm
16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of α-ketoglutarate (α-KG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the
Prdm
16 promoter. AMPKα1 ablation reduced isocitrate dehydrogenase 2 activity and cellular α-KG levels. Remarkably, postnatal AMPK activation with AICAR or metformin rescued obesity-induced suppression of brown adipogenesis and thermogenesis. In summary, AMPK is essential for the epigenetic control of BAT development through α-ketoglutarate, thus linking a metabolite to progenitor cell differentiation and thermogenesis.
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Details
- Title
- AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis
- Creators
- Qiyuan Yang - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Xingwei Liang - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Xiaofei Sun - School of Food Sciences, Chinese Academy of Agricultural Sciences, Washington State University, Pullman, WA 99164Lupei Zhang - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Xing Fu - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Carl J Rogers - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Anna Berim - Institute of Biological Chemistry, Washington State University, Pullman, WA 99164Shuming Zhang - School of Food Sciences, Chinese Academy of Agricultural Sciences, Washington State University, Pullman, WA 99164Songbo Wang - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Bo Wang - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Marc Foretz - INSERM U1016, Institut Cochin, Paris, FranceBenoit Viollet - INSERM U1016, Institut Cochin, Paris, FranceDavid R Gang - Institute of Biological Chemistry, Washington State University, Pullman, WA 99164Buel D Rodgers - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164Meijun Zhu - School of Food Sciences, Chinese Academy of Agricultural Sciences, Washington State University, Pullman, WA 99164Min Du - Washington Center for Muscle Biology and Department of Animal Sciences, Washington State University, Pullman, WA 99164
- Publication Details
- Cell metabolism, Vol.24(4), pp.542-554
- Academic Unit
- Animal Sciences, Department of; Pharmaceutical Sciences, Department of; Biological Chemistry, Institute of; Food Science, School of
- Identifiers
- 99900547510701842
- Language
- English
- Resource Type
- Journal article