Vitamin D and Development Origins of Obesity and Insulin Resistance

维生素 D 与肥胖和胰岛素抵抗的发育起源

• 批准号: 10589302
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589302
• 关键词: 10 year old; Address; Adipocytes; Adipose tissue; Age; Area; Award; Birth; Blood specimen; Body mass index; Bone Marrow; Breast Feeding; Cardiovascular Diseases; Caring; Cells; Child; Development; Diabetes Mellitus; Early treatment; Eating; Eligibility Determination; Embryo; Embryonic Induction; Energy Metabolism; Environmental Risk Factor; Epigenetic Process; Expenditure; Family; Family member; Fatty acid glycerol esters; Fibroblasts; First Pregnancy Trimester; Future; General Population; Genetic; Growth; Health; Health Personnel; Health system; Hematopoietic stem cells; Human; Hypertension; Hypertriglyceridemia; Immune; In Vitro; Incidence; Infant; Infiltration; Insulin Resistance; Life; Macrophage; Measures; Metabolic; Metabolic Diseases; Methylation; Military Personnel; Mothers; Multivitamin; Mus; Myeloid Cells; Obesity; Overweight; Pathway interactions; Pattern; Phenotype; Placebos; Population; Predisposition; Pregnancy; Pregnant Women; Prevalence; Process; Proliferating; Randomized, Controlled Trials; Risk; Role; Serum; Stimulus; Sun Exposure; Supplementation; System; Testing; Tissue Differentiation; Tissue Expansion; Tissues; Transfection; Transplantation; Umbilical Cord Blood; Up-Regulation; Veterans; Vitamin D; Vitamin D Deficiency; Vitamin D supplementation; Vitamin Deficiency; Weight; Weight Gain; Woman; active duty; adipocyte differentiation; antenatal; cardiovascular risk factor; child bearing; cohort; disorder risk; early pregnancy; early screening; fetal; immunoregulation; improved; in utero; maternal obesity; military service; monocyte; obese person; obesity development; obesity prevention; obesity risk; offspring; offspring obesity; postnatal; pregnant; prenatal; prevent; programs; recruit; screening; specific biomarkers; systemic inflammatory response; young adult

early 80% of the Veterans are either overweight or obese, increasing their risk of hypertension, diabetes, and cardiovascular disease. Accumulation of excess adiposity in this population begins at an early age, as nearly 20% of young active-duty veterans are obese, suggesting that this metabolic derangement starts early in life. We aim to identify genetic programs induced by environmental conditions that increase veterans' susceptibility to the development of obesity. We have collected convincing evidence suggesting that that a high incidence of vitamin D (VD) insufficiency in young veterans and their offspring at birth could have significant long-term consequences on their obesity risk. In mice, offspring from VD deficient dams become more obese with increased insulin resistance (IR) and systemic inflammation by 6 weeks despite postnatal VD supplementation. Furthermore, transplantation of fetal hematopoietic stem cells (HSCs) from VD-deficient embryos induces higher weight and IR in VD-sufficient recipient mice during their life suggesting the involvement of persistent epigenetic immune cell programming. We found that in utero VD deficiency suppresses HSC Jarid2 expression activating the Mef2/PGC1D pathway, which persists in recipient bone marrow, resulting in adipose macrophage miR106b-5p secretion, which promotes adipose IR. It is unclear, however, if VD supplementation in utero can prevent the onset of this epigenetic program and if this program drives adipocyte proliferation and differentiation. Importantly, our significant findings from the VDAART randomized controlled trial study in 529 pregnant women supplemented from the first trimester with 4000IU/d suggest that children from VD supplemented mothers have a 10% lower BMI starting at age 4. Moreover, maternal VD supplementation decreased the projected risk of obesity at young adult life by 15-fold, suggesting that VD supplementation early in life reduces future risk of metabolic disease. We hypothesize that VD supplementation early in pregnancy prevents epigenetic suppression of Jarid2 and Mef2/PGC1D activation, thereby reducing miR106b-5p secretion from myeloid cells and preventing adipose tissue differentiation. To test this hypothesis, we propose in Aim1a to determine if early VD supplementation in VD deficient pregnant dams prevents induction of the HSC Jarid2/PGC1D/miR106b-5p program and the transplantation of obesity and IR by HSCs into VD sufficient recipient mice. In Aim 1b and 1c, we will determine if Jarid2-null HSCs can transplant obesity and IR to VD-sufficient recipients and if miR106b- null VD-deficient HSCs lack the capacity to transplant obesity and IR, respectively. In Aim 2, we will 1) characterize the mechanisms involved in the lowering of child BMI induced by VD supplementation during early pregnancy by obtaining in our VDAART cohort measures of the obese phenotype (fat distribution, energy expenditure, food intake) and 2) obtain blood samples to determine if circulating miR106b-5p levels correlates with child BMI and fat percentage and if prenatal VD supplementation prevents monocyte Jarid2/PGC1D/miR106b-5p activation and reduces adipocyte differentiation in vitro. The results of this proposal will provide veterans' health providers with evidence for an early screening protocol with specific biomarkers and related pathways that identify veterans at risk of obesity and diabetes. N

早期80%的退伍军人超重或肥胖，增加了他们患高血压、糖尿病和 心血管疾病在这个人群中，过度肥胖的积累开始于幼年，因为几乎 20%的年轻现役退伍军人肥胖，这表明这种代谢紊乱在生命早期就开始了。 我们的目标是确定由环境条件诱导的遗传程序，这些遗传程序增加了退伍军人的易感性。 肥胖症的发展。我们已经收集到令人信服的证据表明， 维生素D（VD）不足的年轻退伍军人和他们的后代在出生时可能有显着的长期 肥胖风险的后果。在小鼠中，VD缺陷母鼠的后代变得更加肥胖， 增加胰岛素抵抗（IR）和全身炎症6周，尽管出生后VD补充。 此外，移植来自VD缺陷胚胎的胎儿造血干细胞（HSC）可诱导 VD充足的受体小鼠在其生命期间的体重和IR较高，表明持续性 表观遗传免疫细胞编程我们发现，在子宫内VD缺乏抑制HSC Jarid 2表达， 激活Mef 2/PGC 1D通路，该通路持续存在于受体骨髓中，导致脂肪巨噬细胞 miR 106 b-5 p分泌，促进脂肪IR。然而，尚不清楚子宫内补充VD是否可以 阻止这一表观遗传程序的启动，如果这一程序驱动脂肪细胞增殖和分化。 重要的是，我们在529名孕妇中进行的VDAART随机对照试验研究的重要发现 从孕早期开始补充4000 IU/d表明，补充VD的母亲所生的儿童 从4岁开始体重指数降低10%。此外，母亲VD补充剂降低了预测的风险， 年轻成年时肥胖的风险降低了15倍，这表明在生命早期补充VD可以降低未来肥胖的风险。 代谢性疾病我们假设，在怀孕早期补充VD可以防止表观遗传 抑制Jarid 2和Mef 2/PGC 1D活化，从而减少骨髓细胞的miR 106 b-5 p分泌 并防止脂肪组织分化。为了验证这一假设，我们在Aim 1a中提出， VD缺陷妊娠母鼠中VD补充可防止HSC Jarid 2/PGC 1D/miR 106 b-5 p的诱导 方案和将肥胖和IR的HSC移植到VD充足的受体小鼠中。在目标1b和1c中， 我们将确定Jarid 2-null HSC是否可以将肥胖和IR移植到VD充足的受体，以及miR 106 b- 无VD缺陷的HSC分别缺乏移植肥胖和IR的能力。在目标2中，我们将1） 描述在早期阶段补充VD诱导儿童BMI降低的机制， 通过在我们的VDAART队列中获得肥胖表型（脂肪分布、能量 2）获得血液样品以确定循环miR 106 b-5 p水平是否相关 与儿童BMI和脂肪百分比有关，如果产前VD补充剂阻止单核细胞 Jarid 2/PGC 1D/miR 106 b-5 p激活并减少体外脂肪细胞分化。这一提议的结果 将为退伍军人的医疗服务提供者提供证据， 以及相关的途径来识别有肥胖和糖尿病风险的退伍军人。 N