AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis.
AMPK/α-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis.
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DOI：
10.1016/j.cmet.2016.08.010
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发表时间：
2016-10-11
期刊：
影响因子：
29
通讯作者：
Du M
中科院分区：
文献类型：
--
作者：
Yang Q;Liang X;Sun X;Zhang L;Fu X;Rogers CJ;Berim A;Zhang S;Wang S;Wang B;Foretz M;Viollet B;Gang DR;Rodgers BD;Zhu MJ;Du M
促进棕色脂肪组织（BAT）发育是治疗肥胖的有吸引力的策略，因为活化的BAT通过产热耗散能量;然而，控制BAT形成的机制尚未完全了解。我们假设，作为能量代谢的主要调节因子，AMPK可能在此过程中发挥直接作用，并发现AMPKα1（PRKAA 1）消融降低了Prdm 16表达并损害了BAT发育。在早期棕色脂肪形成过程中，α-酮戊二酸（α-KG）（TET介导的DNA去甲基化所需的关键代谢物）的细胞水平显著增加，并且是Prdm 16启动子的活性DNA去甲基化所必需的。AMPKα1消融降低异柠檬酸脱氢酶2活性和细胞α-KG水平。值得注意的是，出生后AMPK激活AICAR或二甲双胍挽救了肥胖诱导的棕色脂肪生成和产热抑制。总之，AMPK通过α-酮戊二酸对BAT发育的表观遗传控制至关重要，从而将代谢产物与祖细胞分化和产热联系起来。
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 Prdm16 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 Prdm16 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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影响因子：
29
作者：
Harms MJ;Ishibashi J;Wang W;Lim HW;Goyama S;Sato T;Kurokawa M;Won KJ;Seale P
通讯作者：
Seale P
影响因子：
11.5
作者：
Kron, Ken;Trudel, Dominique;Bapat, Bharati
通讯作者：
Bapat, Bharati
DOI：
10.1056/nejmra0803836
发表时间：
2009-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kinney HC;Thach BT
通讯作者：
Thach BT
影响因子：
29
作者：
Martínez de Morentin PB;González-García I;Martins L;Lage R;Fernández-Mallo D;Martínez-Sánchez N;Ruíz-Pino F;Liu J;Morgan DA;Pinilla L;Gallego R;Saha AK;Kalsbeek A;Fliers E;Bisschop PH;Diéguez C;Nogueiras R;Rahmouni K;Tena-Sempere M;López M
通讯作者：
López M
影响因子：
64.5
作者：
Cohen P;Levy JD;Zhang Y;Frontini A;Kolodin DP;Svensson KJ;Lo JC;Zeng X;Ye L;Khandekar MJ;Wu J;Gunawardana SC;Banks AS;Camporez JP;Jurczak MJ;Kajimura S;Piston DW;Mathis D;Cinti S;Shulman GI;Seale P;Spiegelman BM
通讯作者：
Spiegelman BM