Maternal B-vitamin status during development and programming of adult offspring adiposity

Developmental programming suggests that perinatal environmental conditions can impact risk for chronic diseases. Population studies have reported greater insulin resistance and adiposity in offspring from mothers with adequate folate but low vitamin B12 (B12) status during pregnancy. Rodent studies have reported that these effects are sex-specific. Folate, a methyl nutrient, is metabolically linked to B12. Low B12 status, even when folate is adequate, can trap folate in a metabolically inactive form. Folate deficiency is rare in Canada due to folic acid fortification of grains, yet one in 20 Canadians are estimated to be B12-deficient. The objective of this thesis is to determine the mechanisms underlying the relationship between maternal B-vitamin status during pregnancy and offspring adiposity and glucose homeostasis. In vitro experiments assessed direct effects of folic acid on adipocyte energy metabolism. In 3T3-L1 adipocytes, cells treated with 1.6μM folic acid had lower (p≤0.05) mitochondrial respiration rates than cells treated with 0.16μM folic acid. Adipocytes treated with 1.6μM 5-methyltetrahydrofolate (5-MTHF), the circulating form of folate, had higher (p≤0.01) mitochondrial respiration rates than cells treated with 0.16μM 5-MTHF. Female mice (C57BL/6J) were fed one of three maternal diets six weeks prior to breeding and through pregnancy/lactation: control (M-CON), supplemental folic acid with adequate B12 (SFA+B12), or SFA without B12 (SFA-B12). One male and one female from each dam were weaned onto either a control or western diet (45% kcal fat). Sex-specific differences by maternal diet were observed in the offspring. Female control-fed SFA-B12 offspring had lower (p≤0.05) serum IGF-1 (insulin-like growth factor-1) concentrations than M-CON and SFA+B12 offspring. This was accompanied by higher (p≤0.05) hepatic Cpt1a mRNA in SFA-B12 and SFA+B12 offspring than M-CON offspring. Female western-fed SFA+B12 offspring had higher (p≤0.05) hepatic FADS2 and ELOVL2 protein than M-CON offspring. Conversely, male control-fed SFA-B12 offspring had higher (p≤0.05) hepatic linoleic acid (C18:2n-6) and lower (p≤0.05) eicosapentaenoic acid (C20:5n-3) concentrations, and lower (p=0.08) hepatic ELOVL2 protein than M-CON offspring. These findings suggest programming of offspring adiposity and glucose homeostasis by maternal B-vitamin status occurs through sex-specific alterations in IGF-1, and adipose tissue and hepatic lipid metabolism.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat