Investigating the role of metabolic programming in vitamin D deficiency induced adiposity

摘要 怀孕期间维生素D缺乏症很普遍（在美国高达91%）。流行病学研究 和啮齿动物模型表明，维生素D缺乏在发展（DVD）导致增加 肥胖和代谢功能障碍。新的研究表明，这些影响可以持续到成年， 恢复维生素D充足。这意味着发展规划，一种机制， 发育过程中的负面事件导致由于表型稳定的“编程”而持续存在的效应。 应答在这里，我们建议建立在我们实验室的新发现的基础上，即遗传上不同的个体 对DVD的持续影响的敏感性。我们将讨论三个重要的问题， DVD在肥胖症发育程序中的作用：（1）DVD干扰哪些代谢过程， 改变肥胖？(2)DNA甲基化失调是DVD效应持续存在的机制吗？ 成年？和（3）哪些基因和/或表型突变是易感性差异的原因。这些 这些发现将为改善DVD的诊断和干预提供关键的机制证据， 诱发肥胖及相关影响。此外，本研究将有助于鉴定敏感性 这些因素可能作为预防性治疗的长期结果的有价值的早期检测生物标志物， 措施，测试治疗效果的目标，以及改进研究设计的驱动因素， 对人类的发现。

ABSTRACT Vitamin D deficiency during pregnancy is prevalent (up to 91% in the United States). Epidemiological studies and rodent models demonstrate that vitamin D deficiency during development (DVD) leads to increased adiposity and metabolic dysfunction. Emerging studies show these effects can persist into adulthood despite restoration of vitamin D sufficiency. This implicates developmental programming, a mechanism by which negative events during development cause effects that persist due to stable “programming” of phenotypic responses. Here, we propose to build on novel findings from our lab that genetically divergent individuals differ in susceptibility to the persistent effects of DVD. We will address three important questions regarding the role of DVD in developmental programming of adiposity: (1) Which metabolic processes are perturbed by DVD to alter adiposity?; (2) Is dysregulation of DNA methylation a mechanism of persistence of DVD effects into adulthood?; and (3) Which genes and/or epimutations are responsible for differences in susceptibility. These findings will provide mechanistic evidence that is critical for improving diagnoses and interventions of DVD- induced obesity and related effects. Furthermore, this study will facilitate the identification of susceptibility factors that will likely serve as valuable early detection biomarkers of long-term outcomes for preventative measures, targets for testing efficacy of treatments, and drivers of improved study design in translating our findings to human populations.