DNA 5-hydroxymethylcytosine (5hmC), converted from 5-methylcytosine (5mC), is highly enriched in the central nervous system and is dynamically regulated during neural development and metabolic disorders. However, whether and how neural 5hmC is involved in metabolic disorders shows little evidence. In this study, significant downregulation of the DNA 5hmC were observed in the cerebral cortex of HFD-induced diabetic mice, while phosphated AMP-activated protein kinase (p-AMPK) and ten-eleven translocation 2 (TET2) reduced, and mitochondrial dysfunction. We futher demonstrated that dysregulation of 5hmC preceded mitochondrial dysfunction in palmitic acid-treated HT22 cells and decreased level of 5hmC led to mitochondrial respiratory activity and apoptosis in HT22 cells. Taken together, our results reveal that neural 5hmC undergoes remodeling during HFD-induced metabolic disorder, and 5hmC downregulation significantly impacts on mitochondrial respiration and cell apoptosis. This study suggests a novel link between metabolic disorder and neural impairment through neural DNA 5hmC remodeling and resultant mitochondrial dysfunction.

中文翻译：

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DNA 5-羟甲基胞嘧啶的下调与高脂饮食诱导的糖尿病小鼠的线粒体功能障碍和神经元损伤有关。

从5-甲基胞嘧啶（5mC）转换而来的DNA 5-羟甲基胞嘧啶（5hmC）在中枢神经系统中高度富集，并在神经发育和代谢紊乱中受到动态调节。但是，神经5hmC是否以及如何参与代谢紊乱显示很少的证据。在这项研究中，在HFD诱导的糖尿病小鼠的大脑皮层中观察到DNA 5hmC的显着下调，而磷酸化的AMP激活的蛋白激酶（p-AMPK）和十一个十一易位2（TET2）减少，线粒体功能障碍。我们进一步证明，棕榈酸处理的HT22细胞中5hmC的失调先于线粒体功能障碍，而5hmC的水平降低导致HT22细胞的线粒体呼吸活性和细胞凋亡。在一起 我们的研究结果表明，神经元5hmC在HFD诱发的代谢紊乱中会发生重塑，而5hmC下调会对线粒体呼吸和细胞凋亡产生显着影响。这项研究提出了通过神经DNA 5hmC重塑和由此导致的线粒体功能障碍，在代谢紊乱和神经损伤之间建立新的联系。