Biological Effects of Folate/Cobalamin Imbalance in Mammals

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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.