Type 2 diabetes (T2DM) is the leading cause of death and disability worldwide. Nearly one in four veterans have T2DM and this prevalence is estimated to increase to 36% by 2025. Lifestyle interventions aiming at weight loss are successful at reducing risk of diabetes but long-term weight-maintenance strategies have been found to be unsustainable. More interestingly, substantial diabetes risk (~40-50%) remains even after successful weight loss, suggesting that other determinants play a role in disease susceptibility. Multiple studies provide evidence for the hypothesis that environmental factors in utero affect patterns of fetal and infant growth that result in increased susceptibility to insulin resistance (IR) and metabolic disorders later in life. Approximately one million veterans are women of childbearing age and half are vitamin D-deficient. Vitamin D deficiency during pregnancy has been linked to IR in prepubertal children. However, no prior interventional studies in humans have evaluated the effects of antenatal vitamin D supplementation on offspring IR and metabolic complications. In rodents, maternal vitamin D deficiency results in a pro-inflammatory immune cell program in the offspring and increased levels of systemic inflammatory cytokines prior to the development of IR. Postnatal vitamin D supplementation does not reverse any of these immune or metabolic changes, suggesting that persistent epigenetic programming of immune cells is involved. Our preliminary data shows for the first time that IR is transplantable. Hematopoietic stem cells (HSCs) from fetuses subjected to vitamin D deficiency in utero confer permanent IR and shift bone marrow (BM) hematopoiesis toward greater progenitors and myeloid cells in vitamin D-sufficient adult mice, implying epigenetic immune reprogramming. Methylation analysis of BM from recipients of vitamin D-deficient vs. ?sufficient HSCs identified multiple differentially methylated regions. This project focuses on a hypermethylated region in the promoter of Jarid2, a methyltransferase known to be upregulated by active vitamin D. Analysis of corresponding gene expression data identified that regulation of the Mef2-PGC1?-miR106b network by Jarid2 could be a potential pathway mediating the immunometabolic phenotype. Thus, we hypothesize that Jarid2 suppression and PGC1? upregulation in HSCs during embryogenesis program myeloid cells to promote IR, and that this process can be reversed with maternal antenatal vitamin D supplementation. To test this epigenetic immune program in vivo, we propose to determine the influence of altering myeloid expression of the Jarid2/PGC1?/miR106b pathway in mice on the development of IR. Additionally, we will utilize a unique opportunity to obtain human samples and data from the multicenter Vitamin D Antenatal Asthma Reduction Trial (VDAART) to determine the role of antenatal vitamin D supplementation (4000 IU/d vs. placebo) in offspring IR and metabolic outcomes later in life. Findings from these studies are likely to delineate novel concepts by which immune cells are programmed to induce IR, and could provide the basis for early screening of vitamin D levels before and early in pregnancy, as well as more aggressive routine supplementation. . !
Type 2 diabetes is the leading cause of death and disability worldwide. Multiple studies hypothesize that environmental factors in utero program patterns of fetal and infant growth that result in increased susceptibility to insulin resistance later in life. We found that transplanted hematopoietic stem cells from embryos exposed to vitamin D deficiency in utero are capable of transferring insulin resistance to vitamin D-sufficient adult mice. In this application we will explore the role of macrophages and their genetic program that we have implicated in the development of adipose tissue insulin resistance induced by vitamin D deficiency in utero, as well as evaluating whether antenatal vitamin D supplementation in humans reduces insulin resistance in the offspring. Our results will provide a better understanding of the programming of immune cells in utero as they contribute to the origins of insulin resistance and potentially highlight a need for more aggressive screening and treatment of vitamin D deficiency during pregnancy. !
| Oh, Jisu; Riek, Amy E; Zhang, Rong M et al. (2018) Deletion of JNK2 prevents vitamin-D-deficiency-induced hypertension and atherosclerosis in mice. J Steroid Biochem Mol Biol 177:179-186 |
| Riek, Amy E; Oh, Jisu; Darwech, Isra et al. (2018) Vitamin D3 supplementation decreases a unique circulating monocyte cholesterol pool in patients with type 2 diabetes. J Steroid Biochem Mol Biol 177:187-192 |
