Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue.
Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue.
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DOI：
10.2337/db12-0548
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发表时间：
2013-03
期刊：
影响因子：
7.7
通讯作者：
Crestani M
中科院分区：
文献类型：
--
作者：
Galmozzi A;Mitro N;Ferrari A;Gers E;Gilardi F;Godio C;Cermenati G;Gualerzi A;Donetti E;Rotili D;Valente S;Guerrini U;Caruso D;Mai A;Saez E;De Fabiani E;Crestani M
染色质修饰对环境和营养刺激很敏感。表观遗传调控异常与代谢紊乱有关，如肥胖和糖尿病，这些代谢紊乱通常与氧化代谢缺陷有关。在这里，我们评估了类特异性组蛋白去乙酰化酶（HDACs）合成抑制剂的潜力，中心染色质重塑酶，以改善代谢功能障碍。用i类特异性HDAC抑制剂处理的培养肌管和原代棕色脂肪细胞显示出更高的Pgc-1α表达，线粒体生物发生增加，耗氧量增加。用I类选择性而非ii类选择性HDAC抑制剂治疗肥胖糖尿病小鼠，可增强骨骼肌和脂肪组织的氧化代谢，促进能量消耗，从而降低体重、葡萄糖和胰岛素水平。这些作用可归因于骨骼肌中Pgc-1α作用的增加和脂肪组织中PPARγ/ Pgc-1α信号的增强。体内ChIP实验表明，抑制HDAC3可能是i类选择性HDAC抑制剂有益作用的原因。这些结果表明，I类HDAC抑制剂可能为治疗2型糖尿病提供了一种药理学方法。
Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I–specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I– but not a class II–selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1α action in skeletal muscle and enhanced PPARγ/PGC-1α signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I–selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes.
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影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
7.7
作者：
Li H;Gao Z;Zhang J;Ye X;Xu A;Ye J;Jia W
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Jia W
影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
4.8
作者：
Haberland, Michael;Carrer, Michele;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
4.8
作者：
Gao, L;Cueto, MA;Atadja, P
通讯作者：
Atadja, P