Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes
Abstrak
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.
Topik & Kata Kunci
Penulis (22)
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. Head
Mark S. Sands
Carlos Bernal-Mizrachi
Akses Cepat
- Tahun Terbit
- 2023
- Sumber Database
- DOAJ
- DOI
- 10.1038/s41467-023-38849-z
- Akses
- Open Access ✓