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

摘要 妊娠期维生素D缺乏症很普遍(在美国，维生素D缺乏率高达91%)。流行病学研究 啮齿动物模型表明，发育期间维生素D缺乏(DVD)会导致 肥胖症和代谢紊乱。新出现的研究表明，这些影响可以持续到成年，尽管 恢复维生素D供给量。这牵涉到发展规划，这是一种通过 发育过程中的负面事件造成的影响持续存在，这是由于表型的稳定“编程”造成的 回应。在这里，我们建议建立在我们实验室的新发现基础上，即遗传差异的个体不同 易受DVD的持久影响。我们将解决关于角色的三个重要问题 DVD在肥胖症的发育规划中的作用：(1)DVD干扰哪些代谢过程 改变肥胖？；(2)DNA甲基化异常是DVD效应持续存在的机制 成年期？以及(3)哪些基因和/或表型突变导致了易感性的差异。这些 这些发现将提供机械证据，这些证据对于改善DVD的诊断和干预至关重要。 诱导性肥胖及其相关影响。此外，这项研究将有助于确定易感性。 可能作为预防性治疗长期结果的有价值的早期检测生物标志物的因素 测试治疗有效性的措施、目标和改进研究设计的驱动因素 对人类的研究结果。

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.