Biological Effects of Folate/Cobalamin Imbalance in Mammals

自1998年以来，强制性强化谷物产品已实施，以减少神经管出生缺陷的发生率。这一政策取得了成功，但提高了人口的叶酸水平。叶酸是DNA合成和甲基代谢所必需的维生素。叶酸的代谢与其他几种甲基营养素有关，并依赖于充足的维生素B12 （B12或钴胺素）状态。食品供应中没有强化B12在加拿大人群中B12水平低下是很常见的。高叶酸摄入量与低B12状态的潜在不利影响仍不确定。我们研究项目的长期目标是确定叶酸和B12失衡的代谢和生理影响。在我们的发现基金（2009-2014）任期内，我们的研究主要集中在三个关键领域，并完成了以下工作：i)描述了母体高叶酸摄入量与低B12状态下发育暴露的分子和生理影响；Ii)鉴定甲基营养素在机体组成、葡萄糖稳态和心血管功能中的新颖/非传统生理作用；iii)确定不同补充形式的叶酸[叶酸与甲基四氢叶酸（MTHF）]的分子和代谢作用。这些发现是我们续期申请的基础。我们的更新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，这些机制是可遗传的，但可能是可逆的，基因表达的调节剂，包括DNA甲基化和染色质修饰（例如，甲基化和乙酰化）。目的1：确定甲基营养素代谢在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的分子作用。我们已经证明，有针对性地破坏半胱硫氨酸-ß-合成酶（Cbs +/-）的小鼠更容易受到高脂肪饮食（HFD）诱导的肥胖增加和葡萄糖代谢和心脏脂质代谢紊乱的影响。本研究将扩展这些发现，确定这些影响的潜在机制，并进一步描述甲基营养代谢（和Cbs）在身体成分、葡萄糖代谢和心脏脂质代谢中的作用。目的2：确定发育暴露于母体高叶酸摄入和低B12状态下影响肥胖、葡萄糖代谢和心血管功能的机制。这些研究将扩展我们的发现，即在高叶酸摄入量和低B12状态的雌性成年后代小鼠中，脂肪、葡萄糖稳态和心血管功能的性别特异性编程。这一目标将集中在确定潜在的机制（针对表观遗传过程）解释这一现象。目的3：确定母体叶酸/B12失衡对肥胖和葡萄糖代谢的影响是否跨代，是否通过表观遗传标记的遗传发生。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。这将告知进一步提高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.