Understanding the Developmental Links: The Role of Vitamin D in Metabolic Disease Risk

A recent study published in the Nature Communications Journal found that transplantation of fetal hematopoietic stem cells (HSCs) intrauterine Vitamin D (VD) deficiency in VD-sufficient mice can induce diabetes.

Research: Fetal vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes. Image credit: urbans/Shutterstock.comstudy: Fetal vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes. Image credit: urbans/Shutterstock.com


According to the genesis hypothesis of adult diseases, environmental factors in the womb Alternatively, they program infant growth patterns early after birth, resulting in predisposition to obesity and insulin resistance (IR) later in life. Therefore, identifying such factors may prove important in developing therapeutic and preventive interventions for future generations.

Genome reprogramming occurs during embryogenesis in response to environmental stimuli. While this may facilitate rapid environmental adaptation, it can also cause lifelong maladaptive changes that predispose individuals to obesity and IR.

According to research, in the uterus, VD deficiency in mice can cause systemic inflammation, excessive fat accumulation, IR and fatty liver in offspring despite postnatal VD supplementation.

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This study showed that transplantation of VD-deficient fetal HSCs into VD-sufficient mice could induce IR. First, we fed C57BL/6 mice and a diet-induced IR mouse model with sufficient VD. [VD(+)] or VD defect [VD(-)] diet 4 weeks before pregnancy The research team isolated fetal liver HSCs from VD(+) and VD(-) maternal animals and transplanted them into 8-week-old VD(+) mice.

After 8 weeks, 90% of peripheral blood cells in both groups and 98% of epididymal immune cells in the stromal vascular fraction after 30 weeks were donor-derived. The authors performed an intraperitoneal insulin and glucose tolerance test. VD(-) HSC recipients exhibited fasting hyperglycemia, IR, and impaired glucose tolerance.

Next, they examined the IR phenotype of primary and secondary transplant recipients. Secondary transplant recipients were VD(+) mice engrafted with bone marrow from VD(+) primary recipients engrafted with VD(-) HSCs. A stable IR phenotype was evident 6 months after transplantation in primary and secondary recipients.

Eight weeks after transplantation, a hyperinsulinemic-euglycemic clamp in primary recipients revealed peripheral IR induction and perigonadal fat as the primary insulin-resistant tissue. This epididymal white adipose tissue (eWAT) was >99% donor-derived and showed immune cell proliferation or infiltration with a predominance of pro-inflammatory M1 macrophages.

Transcriptome analysis showed upregulation and downregulation of 391 and 657 genes in the bone marrow of VD(−) HSC recipients 8 weeks after transplantation. The Jumonji and AT-rich interaction domain 2 (Jarid2) pathways were most prominently activated.

Jarid2 was downregulated in recipient bone marrow and activated downstream genes associated with metabolic function, such as myocyte enhancer factors (Meh 2) and its co-activator (PGC1α).

These changes were also present in eWAT, peritoneal macrophages, and adipose tissue macrophages (ATM) of VD(-) donors and recipients, despite normal plasma VD levels. Several immature microRNAs (miRNAs) were downregulated in myeloid cells of VD(-) HSC recipients. However, mature miRNA levels are elevated in eWAT ATMs, suggesting increased maturation and secretion of macrophage miRNAs, miR-106b-5p highly secreted miRNAs.

Increased miR-106b-5p secretion was also observed in secondary transplant recipients. Transfection of mouse adipocytes with mimics of the most abundant miRNAs identified in ATM revealed significant induction of adipocyte IR by miR-106b-5p and Let-7g-5p.

Adipocytes conditioned to ATM medium of VD(−) HSC recipients and transfected with mir-106b-5p antagomir showed improved insulin sensitivity.

We used computational tools to assess putative conserved targets of miR-106b-5p among insulin signaling genes.

This identified the phosphoinositide-3-kinase (PIK3) regulatory subunit 1 (PIK3R1) gene containing binding sites for the mir-106b-5p family in the 3′ untranslated region (3′ UTR) of both mouse and human. I was. gene.

Transfection of miR-106b-5p mimics into adipocytes resulted in transcription of the p85α and catalytic α (PIK3CA) subunits of PIK3 and the downstream 3-phosphoinositide-dependent protein kinase 1 (PDPK1) required for AKT activation. level has decreased. Western blot analysis confirmed decreased PIK3CA, PIK3R1 and PDPK1 expression and decreased AKT phosphorylation.

Finally, the researchers analyzed 30 healthy pregnant women and their infants to assess whether VD deficiency during pregnancy causes similar HSC reprogramming in humans. They found that two-thirds of newborns were VD-deficient and that cord blood VD levels correlated with birth weight.

Adipocytes exposed to medium conditioned with monocytes in cord blood of VD-deficient mothers showed lower PDPK1, PIK3CA, and PIK3R1 protein levels.

low Jared 2 Although transcript and protein levels are high Mef2/PGC1a Transcript and protein levels were observed in cord blood monocytes from VD-deficient mothers. Cord blood VD levels were inversely correlated with plasma levels of miR-106b-5p.


In summary, this study provided evidence that: in the womb, VD deficiency was sufficient to induce epigenetic reprogramming in HSCs, causing IR when VD was transplanted into sufficient mice.This program has been activated Jarid2/Mef2/PGC1a Pathways within immune cells remained stable throughout differentiation and transplantation.

Similar changes were detected in cord blood monocytes from VD-deficient mothers. This finding warrants clinical trials demonstrating that screening and treating VD-deficient pregnant women reduces the long-term risk of cardiometabolic disease in their offspring.

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