AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis

被引：214

作者：

Yang, Qiyuan ^{[1
,2
]}

Liang, Xingwei ^{[1
,2
]}

Sun, Xiaofei ^{[3
]}

Zhang, Lupei ^{[1
,2
,6
]}

Fu, Xing ^{[1
,2
]}

Rogers, Carl J. ^{[1
,2
]}

Berim, Anna ^{[4
]}

Zhang, Shuming ^{[3
]}

Wang, Songbo ^{[1
,2
]}

Wang, Bo ^{[1
,2
]}

Foretz, Marc ^{[7
,8
,9
]}

Viollet, Benoit ^{[7
,8
,9
]}

Gang, David R. ^{[4
]}

Rodgers, Buel D. ^{[1
,2
]}

Zhu, Mei-Jun ^{[3
]}

Du, Min ^{[1
,2
,5
]}

机构：

[1] Washington State Univ, Washington Ctr Muscle Biol, Pullman, WA 99164 USA

[2] Washington State Univ, Dept Anim Sci, Pullman, WA 99164 USA

[3] Washington State Univ, Sch Food Sci, Pullman, WA 99164 USA

[4] Washington State Univ, Inst Biol Chem, Pullman, WA 99164 USA

[5] China Agr Univ, Beijing Adv Innovat Ctr Food Nutr & Human Hlth, Coll Food Sci & Nutr Engn, Beijing 100194, Peoples R China

[6] Chinese Acad Agr Sci, Inst Anim Sci, Beijing 100193, Peoples R China

[7] Inst Cochin, INSERM, U1016, F-75014 Paris, France

[8] CNRS, UMR 8104, F-75014 Paris, France

[9] Univ Paris 05, Sorbonne Paris Cite, F-75006 Paris, France

来源：

CELL METABOLISM | 2016年 / 24卷 / 04期

关键词：

EMBRYONIC STEM-CELLS; ADIPOSE-TISSUE THERMOGENESIS; INFANT-DEATH-SYNDROME; IDH MUTATIONS; METHYLATION; CANCER; FAT; 5-HYDROXYMETHYLCYTOSINE; EXPRESSION; MITOCHONDRIA;

D O I：

10.1016/j.cmet.2016.08.010

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 AMPK alpha 1 (PRKAA1) ablation reduced Prdm16 expression and impaired BAT development. During early brown adipogenesis, the cellular levels of a-ketoglutarate (alpha KG), a key metabolite required for TET-mediated DNA demethylation, were profoundly increased and required for active DNA demethylation of the Prdm16 promoter. AMPKa1 ablation reduced isocitrate dehydrogenase 2 activity and cellular alpha 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 alpha KG, thus linking a metabolite to progenitor cell differentiation and thermogenesis.

引用

页码：542 / 554

页数：13

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