Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes

Jisu Oh, Amy E. Riek, Kevin T. Bauerle, Adriana Dusso, Kyle P. McNerney, Ruteja A. Barve, Isra Darwech, Jennifer E. Sprague, Clare Moynihan, Rong M. Zhang, Greta Kutz, Ting Wang, Xiaoyun Xing, Daofeng Li, Marguerite Mrad, Nicholas M. Wigge, Esmeralda Castelblanco, Alejandro Collin, Monika Bambouskova, Richard D. HeadMark S. Sands, Carlos Bernal-Mizrachi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from human cord blood have comparable Jarid2/Mef2/PGC1a expression changes and secrete miR-106b-5p, causing adipocyte insulin resistance. These findings suggest that vitamin D deficiency during development has epigenetic consequences impacting the systemic metabolic milieu.

Original languageEnglish
Article number3278
JournalNature communications
Issue number1
StatePublished - Dec 2023


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