Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding
Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding
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DOI：
10.1515/jpm.2010.051
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发表时间：
2010-07-01
影响因子：
2.4
通讯作者：
Dudenhausen, Joachim W.
中科院分区：
文献类型：
--
作者：
Plagemann, Andreas;Roepke, Katharina;Dudenhausen, Joachim W.
目的：产前和新生儿过度喂养方案永久性肥胖和糖尿病倾向，例如，由于诱导下丘脑胰岛素抵抗。我们研究了下丘脑胰岛素受体启动子（IRP） DNA甲基化模式的获得性改变，这可能是一种潜在的分子机制。方法：采用小窝饲养Wistar大鼠，诱导新生儿过饲。下丘脑IRP的cpg -二核苷酸的甲基化用亚硫酸盐测序来绘制。结果：新生儿过度喂养导致早期体重快速增加，导致代谢综合征表型，即肥胖、高瘦素血症、高血糖、高胰岛素血症，胰岛素/葡萄糖比升高。与对照组（n=8； P=0.04）相比，过量喂养的新生大鼠在IRP的322 bp CpG岛中携带任何甲基化CpG残基的动物比例（n=8）有所增加。此外，CpG位点甲基化的平均百分比在SL大鼠中也较高（P=0.01）。两组新生儿血糖水平均与启动子甲基化程度呈正相关（r=0.52； P=0.04）。结论：本研究首次在任何物种和组织中表征了IRP的表观基因组特征。我们的数据显示，由于营养过剩，IRP很容易发生超甲基化，特别是以剂量-反应方式依赖葡萄糖。这典型地表明了营养依赖的表观遗传错误编程的影响，导致“糖尿病”倾向，这可能成为一生的致病性。
Aim: Prenatal and neonatal overfeeding programs a permanent obesity and diabetes disposition, e. g., due to induction of hypothalamic insulin resistance. We investigated acquired alterations of the DNA methylation pattern of the hypothalamic insulin receptor promoter (IRP) which might be an underlying molecular mechanism.Methods: Neonatal overfeeding was induced by rearing Wistar rats in small litters (SL). Methylation of CpG-dinucleotides of the hypothalamic IRP was mapped using bisulfite sequencing.Results: Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperglycemia, hyperinsulinemia, and increased insulin/glucose-ratio. The proportion of animals carrying any methylated CpG residue in the 322 bp CpG island of the IRP was increased in neonatally overfed SL rats (n=8), as compared to controls (n=8; P=0.04). Moreover, the mean percentage of methylated CpG positions was also higher in SL rats (P=0.01). Over both groups, neonatal blood glucose levels were positively correlated to the extent of promoter methylation (r=0.52; P=0.04).Conclusions: This study characterizes for the first time the IRP epigenomically in any species and tissue. Our data reveal that the IRP is vulnerable to hypermethylation due to overnutrition, probably especially glucose-dependent in a dose-response manner. This paradigmatically indicates the impact of nutrient-dependent epigenetic malprogramming, leading to a "diabesity'' disposition which may become pathogenic throughout life.