Biological Effects of Folate/Cobalamin Imbalance in Mammals

1998年开始实施粮食产品的强制性强化，以减少神经管出生缺陷的发生率。这一政策是成功的，但增加了人口的叶酸地位。叶酸是一种合成DNA和甲基代谢所必需的维生素。叶酸的新陈代谢与其他几种甲基营养素有关，并依赖于充足的维生素B12(B12或钴胺)状态。食物供应中没有添加B12，在加拿大人口中，B12状态不佳是很常见的。叶酸摄入量过高与B12状况不佳的潜在不良影响仍不确定。我们研究计划的长期目标是确定叶酸和B12失衡对代谢和生理的影响。在我们的发现基金(2009-2014)任期内，我们的研究集中在三个关键领域，并完成了以下研究：i)表征了B12状况较差的母亲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/非传统生理作用；iii)确定了不同补充形式的叶酸[叶酸与甲基四氢叶酸(MTHF)]的分子和代谢影响。这些调查结果是我们续签申请的基础。我们的续订发现基金的目标是进一步研究甲基营养素在身体组成、葡萄糖动态平衡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，调节基因表达，包括DNA甲基化和染色质修饰(例如，甲基化和乙酰化)。我们的目标将通过以下目标来实现：目标1：确定甲基营养代谢在成年小鼠脂肪组织沉积、葡萄糖稳态调节和心脏脂肪代谢中的分子作用。我们已经证明，定向干扰胱硫醚合成酶(CBS/-)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肪代谢障碍的影响。这一目标将扩大这些发现，并确定解释这些影响的潜在机制，并进一步描述甲基营养代谢(和CBS)在身体组成、葡萄糖代谢和心脏脂肪代谢中的作用。目的2：探讨B12营养不良的母体发育过程中叶酸摄入过高、肥胖、糖代谢和心血管功能受损的机制。这些研究将扩展我们在成年子代小鼠中的肥胖、葡萄糖稳态和心血管功能的性别特异性编程的发现，这些小鼠来自叶酸摄入量高而B12状态较差的雌性小鼠。这一目标将集中于确定导致这一现象的潜在机制(针对表观遗传过程)。目标3：确定通过发育暴露于母体叶酸/B12失衡而导致的肥胖和葡萄糖代谢编程是否是跨代的，并通过表观遗传标记发生。我们的研究将对高叶酸摄入量的代谢和基因组影响提供新的知识，并确定甲基营养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，以及是否有必要重新制定补充剂中叶酸和B12的含量。

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.