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

Author

Listed:
  • Jisu Oh

    (Washington University School of Medicine)

  • Amy E. Riek

    (Washington University School of Medicine)

  • Kevin T. Bauerle

    (Washington University School of Medicine
    VA Medical Center)

  • Adriana Dusso

    (Washington University School of Medicine)

  • Kyle P. McNerney

    (Washington University School of Medicine)

  • Ruteja A. Barve

    (Washington University School of Medicine)

  • Isra Darwech

    (Washington University School of Medicine)

  • Jennifer E. Sprague

    (VA Medical Center)

  • Clare Moynihan

    (Washington University School of Medicine)

  • Rong M. Zhang

    (Washington University School of Medicine)

  • Greta Kutz

    (Washington University School of Medicine)

  • Ting Wang

    (Washington University School of Medicine)

  • Xiaoyun Xing

    (Washington University School of Medicine)

  • Daofeng Li

    (Washington University School of Medicine)

  • Marguerite Mrad

    (Washington University School of Medicine)

  • Nicholas M. Wigge

    (Washington University School of Medicine)

  • Esmeralda Castelblanco

    (Washington University School of Medicine)

  • Alejandro Collin

    (CONICET, Universidad Nacional de Córdoba)

  • Monika Bambouskova

    (Washington University School of Medicine)

  • Richard D. Head

    (Washington University School of Medicine)

  • Mark S. Sands

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Carlos Bernal-Mizrachi

    (Washington University School of Medicine
    VA Medical Center
    Washington University School of Medicine)

Abstract

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.

Suggested Citation

  • 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 X, 2023. "Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38849-z
    DOI: 10.1038/s41467-023-38849-z
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    References listed on IDEAS

    as
    1. Keisuke Tateishi & Yuki Okada & Eric M. Kallin & Yi Zhang, 2009. "Role of Jhdm2a in regulating metabolic gene expression and obesity resistance," Nature, Nature, vol. 458(7239), pages 757-761, April.
    2. J. Oh & S. J. Matkovich & A. E. Riek & S. M. Bindom & J. S. Shao & R. D. Head & R. A. Barve & M. S. Sands & G. Carmeliet & P. Osei-Owusu & R. H. Knutsen & H. Zhang & K. J. Blumer & C. G. Nichols & R. , 2020. "Macrophage secretion of miR-106b-5p causes renin-dependent hypertension," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. A. Young Kim & Yoon Jeong Park & Xuebo Pan & Kyung Cheul Shin & Soo-Heon Kwak & Abdulelah F. Bassas & Reem M. Sallam & Kyong Soo Park & Assim A. Alfadda & Aimin Xu & Jae Bum Kim, 2015. "Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
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