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

Area of Science:

• Immunology
• Metabolic diseases
• Epigenetics

Background:

• Environmental factors, such as vitamin D deficiency, can impact fetal development and increase the risk of metabolic diseases like type 2 diabetes.
• The role of embryonic immune cell programming in the later-life risk of type 2 diabetes remains largely unknown.

Purpose of the Study:

• To investigate whether vitamin D deficiency during embryonic development, specifically in hematopoietic stem cells (HSCs), influences the risk of type 2 diabetes.
• To elucidate the epigenetic mechanisms and molecular pathways involved in this process.

Main Methods:

• Transplantation of vitamin D-deficient fetal HSCs into vitamin D-sufficient recipient mice.
• Analysis of gene expression (Jarid2, Mef2/PGC1a) and microRNA (miR106-5p) in HSCs and adipose tissue macrophages.
• Assessment of insulin resistance in recipient mice and in vitro studies using human cord blood monocytes and adipocytes.

Main Results:

• Vitamin D deficiency in fetal HSCs epigenetically suppressed Jarid2 and activated the Mef2/PGC1a pathway, leading to diabetes in recipient mice.
• These epigenetic changes persisted in recipient bone marrow, causing adipose macrophage infiltration.
• Macrophages secreted miR106-5p, which promoted insulin resistance by repressing PIK3 subunits and down-regulating AKT signaling.
• Similar molecular changes were observed in vitamin D-deficient human monocytes, which induced adipocyte insulin resistance.

Conclusions:

• Vitamin D deficiency during development has lasting epigenetic consequences on immune cells.
• These epigenetic alterations can program an individual for metabolic diseases, specifically type 2 diabetes, through altered macrophage function and insulin resistance.
• The findings highlight a critical window during development where nutritional status can epigenetically influence long-term metabolic health.