Low maternal folic acid during pregnancy exacerbates ectopic fat accumulation in the liver and muscle of male offspring

BACKGROUND: Folic acid (FA), an essential nutrient for one-carbon metabolism, has been implicated in metabolic disease development. Although FA supplementation during pregnancy prevents neural tube defects, its broader metabolic effects remain unclear. METHODS: Eight-week-old C57BL/6 female mice were mated and fed an FA-deficient or control diet during gestation. Male offspring were weaned onto either a normal or Western-type diet, and monitored until 3 months of age. In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort, associations between maternal plasma FA levels during pregnancy and ectopic fat accumulation in offspring at age 6 years were examined. RESULTS: Maternal FA deficiency promoted ectopic fat accumulation in the liver and skeletal muscle of male offspring and increased obesity susceptibility. These effects were associated with disrupted one-carbon metabolism and impaired fatty acid β-oxidation, potentially due to reduced expression of Adenosylmethionine Decarboxylase 1 (Amd1) in male offspring. Consistently, in the GUSTO cohort, maternal plasma FA concentrations were inversely associated with hepatic and muscular fat accumulation in children. CONCLUSION: Maternal FA status plays a critical role in regulating male offspring metabolic health. Maintaining adequate maternal plasma FA levels, rather than focusing solely on dietary intake, may be essential for preventing ectopic fat accumulation in the next generation.