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

  • Cell Rep. 2022 Sep 20;40(12):111381. doi: 10.1016/j.celrep.2022.111381.
Shenlu Qin  1 ,  Yihan Wang  2 ,  Lili Li  2 ,  Junli Liu  2 ,  Congmei Xiao  2 ,  Duo Duan  2 ,  Wanyu Hao  2 ,  Chunxia Qin  2 ,  Jie Chen  2 ,  Luxia Yao  2 ,  Runshuai Zhang  2 ,  Jia You  2 ,  Ju-Sheng Zheng  2 ,  Enzhi Shen  2 ,  Lianfeng Wu  3
Affiliations
  • 1. Fudan University, Shanghai, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
  • 2. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China.
  • 3. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 36130518 DOI: 10.1016/j.celrep.2022.111381
Abstract

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.

Keywords
CP: Developmental biology; CP: Metabolism; DOHaD; SREBP1; adiposity; adulthood disorder; developmental programming; early life; ferroptosis; infertility; lipogenesis; vitamin B12.
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