Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning
Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning
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DOI：
10.1111/bph.13058
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发表时间：
2015-06-01
影响因子：
7.3
通讯作者：
Devarshi, Prasad P.
中科院分区：
文献类型：
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作者：
Henagan, Tara M.;Stefanska, Barbara;Devarshi, Prasad P.
背景与目的丁酸钠（NaB）是一种表观遗传修饰剂，能有效地促进胰岛素敏感性.具体的基因组位点和机制表观遗传诱导的肥胖症和胰岛素抵抗和NaB的目标还没有完全understood.Experimental ApproachThe抗糖尿病和抗肥胖的效果NaB治疗通过比较表型和生理学的C57 BL/6 J小鼠喂食低脂肪饮食（LF），高脂肪饮食（HF）或高脂肪饮食加NaB（HF + NaB）10周。我们通过诱导有益的骨骼肌线粒体适应来确定NaB作用的可能机制，并应用微球菌核酸酶消化和测序（MNase-seq）来评估核小体占据或定位的全基因组差异，并鉴定NaB的相关表观遗传靶点。通过葡萄糖和胰岛素耐量试验测定，改善了胰岛素敏感性，并降低了呼吸交换率。在骨骼肌中，NaB增加了1型纤维的百分比，通过代谢组学测量改善了酰基肉毒碱谱，并产生了由Mnase-seq确定的染色质结构，与LF中所见相似。有针对性的分析代表性的核编码的线粒体基因显示特定的重新定位的-1核小体与改变基因expression.Conclusions and ImplicationsNaB治疗可能是一种有效的药理学方法为2型糖尿病和肥胖症诱导-1核小体重新定位内核编码的线粒体基因，导致骨骼肌线粒体适应，导致更完整的氧化和精益，胰岛素敏感表型。链接Articles这篇文章是一个表观遗传学和治疗的主题部分的一部分。要查看本节中的其他文章，请访问
Background and PurposeSodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood.Experimental ApproachThe anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB.Key ResultsNaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the -1 nucleosome in association with altered gene expression.Conclusions and ImplicationsNaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing -1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete -oxidation and a lean, insulin sensitive phenotype.Linked ArticlesThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit