Multigenerational epigenetic programming induced by paternal obesity and prediabetes

“父亲肥胖和糖尿病前期导致的多代表观遗传规划” 摘要 在美国和其他国家，肥胖及其相关的共病已经达到了流行的程度 这对卫生服务构成了前所未有的挑战。我们发现，一代人 父性肥胖和糖尿病前期计划男性后代有潜在的代谢缺陷，暴露于 营养过剩。潜伏的表型通过父系传播两代，而不会进一步接触 父亲的肥胖。父系传播与预测的精子小RNA的变化有关 来调节转录过程。这种表型的非遗传世代传播可能是 是肥胖风险的重要贡献者，可能需要干预和预防措施 世代繁衍。理解这种可遗传的表观遗传编程的范围和机制 这一现象将在制定管理或预防父亲肥胖影响的新战略方面发挥关键作用。 这项研究有可能确定可用于描述人类综合征的生物标记物。 我们建议确定(1)多代父亲肥胖和糖尿病前期的暴露是否会放大 后代的代谢表型，和/或增加其遗传力；(2) 代谢表型的父系遗传，通过受影响公牛精子的表观遗传学变化；(3) 在早期胚胎中发生的转录变化，以响应精子的表观遗传变化。 环境暴露可以诱导可遗传的表观遗传状态的概念最近得到了很大的认可。 请注意，但对这个主题的理解和记录非常少。我们的实验系统允许直接 对表观遗传模型的检验：可以排除遗传变异是传播的一个因素，因为 我们研究了同基因小鼠，通过父系传播排除了子宫内代谢暴露为 原因，而且代谢表型的高外显性使其易于进行机械性研究。 父性肥胖/糖尿病前期对遗传代谢的意外多代影响 相同的后代挑战了关于肥胖原因的既定观点。这项研究将提供证据证明 肥胖风险有一个与生俱来但非遗传的组成部分，即对肥胖机制的洞察 风险是被创造和传递的，并且是一个服从于进一步研究该现象的系统。

“Multigenerational epigenetic programming induced by paternal obesity and prediabetes” ABSTRACT Obesity and its related co-morbidities have reached epidemic proportions in the United States and other developed countries, posing an unprecedented challenge to health services. We find that a single generation of paternal obesity and prediabetes programs male offspring with a latent metabolic defect that is exposed by overnutrition. The latent phenotype is transmitted paternally for two generations without further exposure to paternal obesity. Paternal transmission is associated with changes in the sperm small RNAs that are predicted to regulate transcriptional processes. This non-genetic transmission of phenotypes across generations may be a significant contributor to the risk of obesity, and may require intervention and prevention measures across multiple generations. Understanding the scope and the mechanism of this heritable epigenetic programming phenomenon will be critical in developing new strategies to manage or prevent the effects of paternal obesity. This study has the potential to identify biomarkers that could be used to characterize the syndrome in humans. We propose to determine (1) if multiple generations of exposure to paternal obesity and prediabetes amplify the metabolic phenotype in subsequent generations, and/or increase its heritability; (2) the mechanism of paternal inheritance of the metabolic phenotype, through epigenetic changes in the sperm of affected sires; (3) the transcriptional changes that occur in the early embryo in response to epigenetic changes in the sperm. The concept that environmental exposures can induce heritable epigenetic states has received much recent attention, but the subject is very poorly understood and documented. Our experimental system permits a direct test of the epigenetic inheritance model: genetic variants can be ruled out as a factor in transmission because we study isogenic mice, transmission through the paternal line rules out in utero metabolic exposure as a cause, and the high penetrance of the metabolic phenotype makes it amenable to mechanistic studies. The unexpected multigenerational effect of paternal obesity/prediabetes on the metabolism of genetically identical offspring challenges established views on the causes of obesity. This study will provide evidence that there is an inborn but non-genetic component to the risk of obesity, insights into the mechanisms by which that risk is created and transmitted, and a system amenable to further study of the phenomenon.