Early-life vitamin B12 orchestrates lipid peroxidation to ensure reproductive success via SBP-1/SREBP1 in Caenorhabditis elegans

• Published in: Cell reports (Cambridge) 2022-09, Vol.40 (12), p.111381-111381, Article 111381
• Main Authors: Qin, Shenlu, Wang, Yihan, Li, Lili, Liu, Junli, Xiao, Congmei, Duan, Duo, Hao, Wanyu, Qin, Chunxia, Chen, Jie, Yao, Luxia, Zhang, Runshuai, You, Jia, Zheng, Ju-Sheng, Shen, Enzhi, Wu, Lianfeng
• Format: Article
• Language: English
• Subjects: adiposity; adulthood disorder; developmental programming; DOHaD; early life; ferroptosis; infertility; lipogenesis; SREBP1; vitamin B12
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111381

Vitamin B12 (B12) deficiency is a critical problem worldwide. Such deficiency in infants has long been known to increase the propensity to develop obesity and diabetes later in life through unclear mechanisms. Here, we establish a Caenorhabditis elegans model to study how early-life B12 impacts adult health. We find that early-life B12 deficiency causes increased lipogenesis and lipid peroxidation in adult worms, which in turn induces germline defects through ferroptosis. Mechanistically, we show the central role of the methionine cycle-SBP-1/SREBP1-lipogenesis axis in programming adult traits by early-life B12. Moreover, SBP-1/SREBP1 participates in a crucial feedback loop with NHR-114/HNF4 to maintain cellular B12 homeostasis. Inhibition of SBP-1/SREBP1-lipogenesis signaling and ferroptosis later in life can reverse disorders in adulthood when B12 cannot. Overall, this study provides mechanistic insights into the life-course effects of early-life B12 on the programming of adult health and identifies potential targets for future interventions for adiposity and infertility. [Display omitted] •Early-life B12 deficiency causes fat level increase and sterility in adult C. elegans•Early-life B12 acts through the methionine cycle-SBP-1/SREBP1 axis•SBP-1/SREBP1 plays a key role in maintaining cellular B12 homeostasis•Repressing lipogenesis or ferroptosis can be late-life options against infertility Qin et al. report that early-life vitamin B12 (B12) programs adult health outcomes in C. elegans. Early-life B12 deficiency results in increased fat deposit and lipid peroxidation that triggers ferroptosis of germ cells in adulthood. Suppression of the SBP-1/SREBP1-lipogenesis-ferroptosis axis in late life can reprogram infertility caused by early-life B12 deficiency.