Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice
Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice
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DOI：
10.1111/j.1365-2443.2009.01326.x
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发表时间：
2009-08-01
期刊：
影响因子：
2.1
通讯作者：
Sakai, Juro
中科院分区：
文献类型：
--
作者：
Inagaki, Takeshi;Tachibana, Makoto;Sakai, Juro
组蛋白H3赖氨酸9(H3K9)甲基化是异染色质形成和转录沉默的重要表观遗传学标志。最近的研究表明，大多数组蛋白赖氨酸的共价修饰是可逆的，并且含有juonji C(JmjC)结构域的蛋白被证明具有这种去甲基酶活性。然而，在完整的动物模型系统中，关于组蛋白赖氨酸去甲基化的生物学作用的信息很少。JHDM2A(JmjC结构域含组蛋白去甲基酶2A，也称为JMJD1A)通过铁和α-酮戊二酸依赖的氧化反应催化H3K9的单甲基化和二甲基化。在这里，我们证明了JHDM2a还调节与能量稳态相关的代谢基因，包括抗脂肪生成、调节脂肪储存、葡萄糖运输和2型糖尿病。缺乏JHDM2a(JHDM2a-/-)的小鼠成年后出现肥胖、高甘油三酯血症、高胆固醇血症、高胰岛素血症和高瘦素血症，这些都是代谢综合征的特征。此外，JHDM2a-/-小鼠表现出快速诱导的低温，表明能量消耗减少，而且呼吸商也较高，表明用于能量生产的脂肪利用较少。这些观察结果可能解释了这些小鼠的肥胖表型。因此，H3K9去甲基酶JHDM2a是参与能量消耗和脂肪储存的基因的关键调节因子，这表明它是以前未被认识的肥胖和代谢综合征的关键调节因子。
Histone H3 lysine 9 (H3K9) methylation is a crucial epigenetic mark of heterochromatin formation and transcriptional silencing. Recent studies demonstrated that most covalent histone lysine modifications are reversible and the jumonji C (JmjC)-domain-containing proteins have been shown to possess such demethylase activities. However, there is little information available on the biological roles of histone lysine demethylation in intact animal model systems. JHDM2A (JmjC-domain-containing histone demethylase 2A, also known as JMJD1A) catalyses removal of H3K9 mono- and dimethylation through iron and alpha-ketoglutarate dependent oxidative reactions. Here, we demonstrate that JHDM2a also regulates metabolic genes related to energy homeostasis including anti-adipogenesis, regulation of fat storage, glucose transport and type 2 diabetes. Mice deficient in JHDM2a (JHDM2a-/-) develop adult onset obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and hyperleptinemia, which are hallmarks of metabolic syndrome. JHDM2a-/- mice furthermore exhibit fasted induced hypothermia indicating reduced energy expenditure and also have a higher respiratory quotient indicating less fat utilization for energy production. These observations may explain the obesity phenotype in these mice. Thus, H3K9 demethylase JHDM2a is a crucial regulator of genes involved in energy expenditure and fat storage, which suggests it is a previously unrecognized key regulator of obesity and metabolic syndrome.