Dnmt3a as an epigenetic mediator of insulin resistance

Dnmt3a 作为胰岛素抵抗的表观遗传介质

基本信息

批准号：
10063521
负责人：
Sona Kang
金额：
$ 37.76万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063521
关键词：
Adipocytes Adipose tissue Aging Agonist Animals Area Biological Biological Markers Body Composition Body Weight Cardiovascular Diseases Cells Chemicals Clinical Complication Cytosine DNA Methylation DNA Modification Methylases DNA Modification Process DNA methylation profiling DNMT3a Data Development Disease Environment Epigenetic Process Etiology Event Family Functional disorder Gene Expression Gene Expression Profiling Gene Expression Regulation Gene Targeting Genes Genetic Epistasis Genetic Transcription Genetic study Goals Health High Fat Diet Human In Vitro Insulin Resistance Knock-in Knockout Mice Lead Mediating Metabolic Metabolism Mitochondria Modification Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Obesity Organism PPAR gamma Pathogenesis Pathogenicity Pathway interactions Pattern Pharmacology Study Positioning Attribute Regulation Repression Research Role Signal Transduction Site Testing Uncertainty adipocyte differentiation base differential expression endoplasmic reticulum stress gene environment interaction glucose tolerance human disease human model improved in vivo insulin mediators insulin sensitivity insulin sensitizing drugs insulin signaling mouse model novel marker promoter response rosiglitazone therapeutic target

项目摘要

Insulin resistance (IR) is the pathophysiological hallmark of type 2 diabetes and obesity. Although several biological pathways have been proposed to be behind IR, there is still a great deal of uncertainty about the mechanisms by which cells and organisms become insulin resistant. The etiology of IR involves intricate interactions between genes and the environment, interactions mediated by epigenetic mechanisms. DNA methylation is a major epigenetic modification that is performed by DNA methyltransferases (Dnmts). Altered patterns of DNA methylation associate with a variety of metabolic perturbations, yet the cause-and-effect relationship remains poorly understood. Our recent studies have demonstrated that IR associates with many locus-specific changes in epigenetic modification. While we were searching for differentially expressed epigenetic modifiers, we discovered that adipose expression of Dnmts was elevated in mouse models of IR and that the increased expression was largely reversed by the insulin sensitizer Rosiglitazone. We have shown that Dnmt3a, in particular among the Dmnt family, is both necessary and sufficient to mediate IR in cultured adipocytes. Consistent with our in vitro results, our primary in vivo studies found that adipose-specific Dnmt3a-knockout mice had improved whole-body insulin sensitivity and glucose tolerance. Furthermore, our gene profiling studies identified Fgf21 as a key target gene repressed by Dnmt3a, with concordant changes in DNA methylation at its promoter. Based on these findings, we hypothesize that adipose Dnmt3a mediates IR by regulating key metabolic genes through altering site-specific DNA methylation at critical cis-regulatory regions. To test our central hypothesis, we will pursue the following aims. Aim 1 is to ascertain the role of Dnmt3a in cell-autonomous IR and to delineate the epistatic relationship of Dnmt3a and PPARγ. Aim 2 is to investigate the full impact of adipose-specific Dnmt3a depletion on whole-body metabolism and to elucidate the underlying mechanisms of the improved insulin sensitivity, and Aim 3 is to elucidate the underlying molecular and epigenetic basis through which Dnmt3a mediates IR using both focused and unbiased approaches. Overall, this research will establish the role of adipose Dnmt3a in the pathophysiology of IR and elucidate the underlying molecular and epigenetic mechanisms. It may also provide novel biomarkers of IR and reveal therapeutic target(s) for IR.

胰岛素抵抗 (IR) 是 2 型糖尿病和肥胖的病理生理学标志，尽管 IR 背后有多种生物学途径，但细胞和生物体产生胰岛素抵抗的机制仍存在很大的不确定性。 IR 涉及基因和环境之间复杂的相互作用，由表观遗传机制介导的相互作用是由 DNA 甲基转移酶 (Dnmts) 进行的主要表观遗传修饰。甲基化与多种代谢扰动相关，但其因果关系仍知之甚少，但我们最近的研究表明，IR 与表观遗传修饰中的许多位点特异性变化相关。我们发现，在 IR 小鼠模型中，Dnmts 的脂肪表达升高，并且胰岛素增敏剂罗格列酮可以在很大程度上逆转这种升高的表达，尤其是 Dnmt3a。与我们的体外结果一致，我们的主要体内研究发现，脂肪特异性 Dnmt3a 敲除小鼠的全身胰岛素敏感性和葡萄糖耐量得到了改善。我们的基因分析研究确定 Fgf21 是 Dnmt3a 抑制的关键靶基因，其启动子处的 DNA 甲基化发生了一致的变化。基于这些发现，我们认识到这一点。脂肪 Dnmt3a 通过改变关键顺式调控区域的位点特异性 DNA 甲基化来调节关键代谢基因。为了检验我们的中心假设，我们的目标 1 是确定 Dnmt3a 在细胞自主 IR 中的作用。并描绘 Dnmt3a 和 PPARγ 的上位关系目标 2 是研究脂肪特异性的全面影响。 Dnmt3a 消耗对全身代谢的影响，并阐明改善胰岛素敏感性的根本机制，目标 3 是阐明 Dnmt3a 使用集中和公正的方法介导 IR 的分子和表观遗传基础。脂肪 Dnmt3a 在 IR 病理生理学中的作用并阐明潜在的分子和表观遗传机制，它还可能提供新的生物标志物。 IR 并揭示 IR 的治疗靶点。