Biological Effects of Folate/Cobalamin Imbalance in Mammals

自1998年以来，对粮食产品进行了强制性强化，以减少神经管出生缺陷的发生率。这项政策取得了成功，但增加了人口的叶酸水平。叶酸是合成DNA和甲基代谢所需的维生素。叶酸的代谢与其他几种甲基营养素有关，并依赖于足够的维生素B12（B12或钴胺素）状态。食物供应没有强化B12和穷人B12状态是常见的加拿大人口。对于B12状态差的高叶酸摄入量的潜在不良影响，仍然没有定论。我们研究计划的长期目标是确定叶酸和B12失衡的代谢和生理影响。在我们的探索基金的任期内，（2009-2014）我们的研究集中在三个关键领域，并完成了以下工作：i）表征了B12状态差的母体高叶酸摄入量对发育的分子和生理影响; ii）确定了甲基营养素在身体组成，葡萄糖稳态和心血管功能中的新型/非传统生理作用;和iii）测定不同补充形式叶酸的分子和代谢作用[叶酸对甲基四氢叶酸（MTHF）]。这些发现是我们续签申请的基础。我们的更新发现补助金的目标是进一步研究甲基营养素在身体组成，葡萄糖稳态和心血管功能中的分子作用/机制，并确定叶酸/B12失衡的影响。我们将重点描述表观遗传机制的作用，表观遗传机制是可遗传的，但可能是可逆的，是基因表达的调节因子，包括DNA甲基化和染色质修饰（如甲基化和乙酰化）。我们的目标将通过以下目的来实现：目的1：确定成年小鼠脂肪组织沉积、葡萄糖稳态调节和心脏脂质代谢中甲基营养代谢的分子作用。我们已经表明，具有针对性破坏胱硫醚-β-合酶（Cbs +/-）（甲基营养代谢所需的酶）的小鼠更容易受到高脂饮食（HFD）诱导的肥胖增加以及葡萄糖代谢和心脏脂质代谢紊乱的影响。本目标将扩展这些发现，并确定解释这些影响的潜在机制，并进一步阐明甲基营养代谢（和CBS）在身体组成，葡萄糖代谢和心脏脂质代谢中的作用。目标2：确定发育期暴露于B12状态差的母亲高叶酸摄入量与肥胖、葡萄糖代谢和心血管功能的关系。这些研究将扩展我们的研究结果的性别特异性编程的肥胖，葡萄糖稳态，和心血管功能的成年后代小鼠从女性叶酸摄入量高，B12状态差。这个目标将集中在确定的潜在机制（针对表观遗传过程）占这一现象.AIM 3：以确定是否编程的肥胖和葡萄糖代谢的发展暴露于母体叶酸/B12不平衡是跨代的，并通过遗传表观遗传标记发生。我们的研究将为高叶酸摄入量的代谢和基因组效应提供新的知识，并确定甲基营养素在生理过程中的新作用。这将告知进一步增加叶酸强化水平的安全性，B12强化的必要性，以及是否需要重新制定补充剂中叶酸和B12的量。

Mandatory fortification of grain products has been implemented since 1998 to reduce the incidence of neural tube birth defects. This policy has been successful but has increased the folate status of the population. Folate is a vitamin required for the synthesis of DNA and for methyl metabolism. The metabolism of folate is linked to several other methyl nutrients, and is dependent on adequate vitamin B12 (B12 or cobalamin) status. The food supply is not fortified with B12 and poor B12 status is common in the Canadian population. Uncertainties remain as to potential adverse effects of high folic acid intakes with poor B12 status. The LONG-TERM GOAL of our research program is to determine the metabolic and physiologic effects of folate and B12 imbalance. During the tenure of our Discovery Grant (2009-2014) our research has focused on three key areas and accomplished the following: i) characterized the molecular and physiological effects of developmental exposure to maternal high folic acid intakes with poor B12 status; ii) identified novel/non-traditional physiological roles for methyl nutrients in body composition, glucose homeostasis, and cardiovascular function; and iii) determined the molecular and metabolic effects of different supplemental forms of folate [folic acid vs methyltetrahydrofolate (MTHF)]. These findings serve as the foundation on which our renewal application is based. The GOAL of our renewal Discovery Grant is to further investigate the molecular roles/mechanisms of methyl nutrients in body composition, glucose homeostasis, and cardiovascular function and to determine the effects of folate/B12 imbalance. We will focus on delineating a role for epigenetic mechanisms, which are heritable, but potentially reversible, regulators of gene expression and include DNA methylation and chromatin modifications (eg, methylation and acetylation). Our goal will be addressed by the following Aims:AIM 1: To determine the molecular role for methyl nutrient metabolism in adipose tissue deposition, regulation of glucose homeostasis, and cardiac lipid metabolism in adult mice. We have shown that mice with targeted disruption of cystathionine-ß-synthase (Cbs +/-), an enzyme required for methyl nutrient metabolism, are more susceptible to high fat diet (HFD)-induced increases in adiposity and disturbances in glucose metabolism and cardiac lipid metabolism. This Aim will extend these findings and determine the underlying mechanisms accounting for these effects and further delineate the role of methyl nutrient metabolism (and Cbs) in body composition, glucose metabolism, and cardiac lipid metabolism. AIM 2: To determine the mechanism by which developmental exposure to maternal high folate intakes with poor B12 status programs adiposity, glucose metabolism, and cardiovascular function. These studies will extend our findings of sex-specific programming of adiposity, glucose homeostasis, and cardiovascular function in adult offspring mice from females with high folic acid intakes and poor B12 status. This Aim will focus on determining the underlying mechanisms (targeting epigenetic processes) accounting for this phenomenon.AIM 3: To determine if the programming of adiposity and glucose metabolism by developmental exposure to maternal folate/B12 imbalance is transgenerational and occurs through of inheritance of epigenetic marks. Our research will contribute new knowledge on the metabolic and genomic effects of high folic acid intakes and define a novel role for methyl nutrients in physiological processes. This will inform as to the safety of further increasing the level of folic acid fortification, the need for B12 fortification, and whether reformulating the amount of folic acid and B12 in supplements is warranted.