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

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

Diabetes Research and Clinical Practice

10.1016/j.diabres.2026.113161

https://doi.org/10.1016/j.diabres.2026.113161

Tomoyo Kawakubo-Yasukochi, Yoshikazu Hayashi, Karen Tan, Koji Kinoshita, Keita Maki, Navin Michael, Suresh Anand Sadananthan, Fabian Yap, Jun Shi Lai, Shohei Yoshimoto, Ayaka Saeki, Ayano Ogura, Kento Minami, Mya Thway Tint, Ena Yano, Soi Kimura, Atsushi Yasukochi, Yi-Chen Lo, Ichiro Takahashi, Sendhil S. Velan, Eijiro Jimi, Johan G. Eriksson, Masato Hirata

14 February 2026

Kawakubo-Yasukochi, T., Hayashi, Y., Tan, K., Kinoshita, K., Maki, K., Michael, N., Sadananthan, S. A., Yap, F., Lai, J. S., Yoshimoto, S., Saeki, A., Ogura, A., Minami, K., Tint, M. T., Yano, E., Kimura, S., Yasukochi, A., Lo, Y.-C., Takahashi, I., … Hirata, M. (2026). Low maternal folic acid during pregnancy exacerbates ectopic fat accumulation in the liver and muscle of male offspring. Diabetes Research and Clinical Practice, 233, 113161. https://doi.org/10.1016/j.diabres.2026.113161

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.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Medical Research Council - Translational & Clinical Research (TCR)
Grant Reference no. : NMRC/TCR/004- NUS/2008; NMRC/TCR/012-NUHS/2014

© 2026 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ).

https://oar.a-star.edu.sg/communities-collections/articles/22868

0168-8227

Institute for Human Development and Potential

https://doi.org/10.1016/j.diabres.2026.113161