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Vitamin D and Developmental Origins of Insulin Resistance

维生素 D 和胰岛素抵抗的发育起源

基本信息

批准号：
10266005
负责人：
Carlos Bernal-Mizrachi
金额：
--
依托单位：
ST. LOUIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266005
关键词：
6 year old Adipose tissue Adult Affect Asthma Blood Pressure Body Weight decreased Body mass index Bone Marrow Candidate Disease Gene Cause of Death Cell Differentiation process Cells Child Chronic Data Development Diabetes Mellitus Disease susceptibility Economics Embryo Embryonic Development Environmental Risk Factor Epigenetic Process Exposure to Female of child bearing age Fetal Liver Gene Expression Gene Expression Profiling Genetic Goals Growth Health Care Costs Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Hypermethylation Immune Incidence Infant Inflammation Inflammatory Insulin Resistance Interleukin-1 Interleukin-6 Intervention Studies Knock-out Lead Life Link Lipids Mediating Metabolic Metabolic Diseases Metabolic syndrome Methylation Methyltransferase Mus Myelogenous Myeloid Cells Nature Non-Insulin-Dependent Diabetes Mellitus Outcome Pathway interactions Pattern Phenotype Placebos Play Predisposing Factor Predisposition Pregnancy Prevalence Quality of life Regulation Resistance Process Risk Rodent Rodent Model Role Sampling Serum Signal Transduction Supplementation System TNF gene Testing Time Transplant Recipients Transplantation Umbilical Cord Blood Up-Regulation Veterans Vitamin D Vitamin D Deficiency Vitamin D supplementation Weight Woman antenatal cytokine diabetes risk disability early screening embryo cell fetal fetus cell improved in utero in utero transplantation in vivo inflammatory marker lifestyle intervention macrophage monocyte negative affect new therapeutic target novel nutrition offspring overexpression postnatal prepuberty prevent programs promoter screening stem cells transplant model weight maintenance

项目摘要

Abstract 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-PGC1α-miR106b network by Jarid2 could be a potential pathway mediating the immunometabolic phenotype. Thus, we hypothesize that Jarid2 suppression and PGC1α 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/PGC1α/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. . !

摘要