Maternal Adipocyte-Derived Exosomes in the Thin-Fat Indian Baby Paradox

摘要 印度是世界上糖尿病患病率最高的国家（2015年有7100万患者）， 低出生体重婴儿人数最多（每年600万至800万）。乍一看，这些似乎 无关的然而，出生体重和成年后患糖尿病的风险之间的关系往往是不确定的。 被描述为“U形”（即低出生体重和高出生体重都会增加个体的成人糖尿病风险）。 与直觉相反，印度的LBW婴儿在出生时具有高脂肪（即体脂百分比）-所谓的“瘦脂肪 印度悖论”这归因于影响胎儿大小和身体组成的多种因素，包括 母亲的瘦脂肪表型、营养不良和肥胖。这些LBW婴儿有高风险， 成人肥胖症和心脏代谢疾病的发展。代际和早期生活（即胎儿和 婴儿）的影响被怀疑是这种风险的基础。一种新的可能性是， 因子穿过胎盘重新编程胎儿心脏代谢发育途径。PIS团队最近 将脂肪细胞来源的外泌体鉴定为能够驱动异常胎儿心脏代谢的母体因子， 发育，已知是肥胖儿童心脏代谢疾病的器官间介导物， 成年人了作为纳米颗粒大小的内吞囊泡，这些外泌体可以穿过胎盘和它们的microRNA。 内容物被预测改变发育途径基因表达。因为我们开发了技术 从体液中分离这些外泌体，我们这项应用的总体目标是测试 在现有研究的基础上， 在印度进行前瞻性多中心研究的能力。我们将通过使用临床数据和 来自印度母婴对的生物标本是一项纵向队列研究（当前n=288）的一部分， 爱德华国王纪念医院，印度浦那美印小组为此生成了初步数据 在PI最近访问印度期间，我们的中心假设是，降低孕产妇和 脐带血脂肪细胞来源的靶向脂肪生成的外泌体microRNA与高婴儿肥胖相关 肥胖症事实上，我们的初步数据支持母体肥胖/肥胖抑制microRNA， 靶向脂肪生成途径成员，并因此被预测导致胎儿脂肪生成增加。 该研究小组由NIH和印度资助的研究人员组成，他们在所有领域都具有国际专业知识。 相关领域。丰富的队列生物储存库是这种不断发展的合作的主要资产。的 该研究与PAR-16-052 -全球非传染性疾病和 终生伤害：探索性研究（R21）：“支持与当地相关的催化性试点研究”; 和“支持制定诊断、预防、治疗和实施战略”。我们的长期 我们的目标是改变目前对儿童肥胖和心脏代谢的发病机制的看法， 疾病此外，该项目有可能确定潜在的治疗目标，用于一级预防， 这些疾病在印度和美国，奠定了基础，更全面的研究 该计划丰富了知识基础，并导致更多的研究建议，以美国国立卫生研究院和其他 来自美国和印度的资助者。

Abstract India has the highest prevalence of diabetes in the world (71 million patients in 2015) and is home to the largest number of low birth weight (LBW) infants (6-8 million per year). At first glance, these may seem unrelated. However, the association between birthweight and eventual risk of diabetes as an adult is often described as “U-shaped” (i.e. both low and high birthweight increase adult diabetes risk for an individual). Counterintuitively, Indian LBW infants have high adiposity (i.e. percent body fat) at birth - the so-called “thin-fat Indian paradox.” This is ascribed to multiple factors which influence fetal size and body composition, including a maternal thin-fat phenotype, undernutrition, and glycemia. These LBW infants are at high risk for development of adult adiposity and cardiometabolic diseases. Intergenerational and early life (i.e. fetal and infantile) influences are suspected to underlie this risk. A novel possibility is that an adiposity-related maternal factor crosses the placenta to reprogram fetal cardiometabolic developmental pathways. The PIs team recently identified adipocyte-derived exosomes as a maternal factor capable of driving abnormal fetal cardiometabolic development and known to be an interorgan mediator of cardiometabolic diseases in obese children and adults. As nanoparticle-sized endocytic vesicles, these exosomes can cross the placenta and their microRNA contents are predicted to alter developmental pathway gene expression. Because we developed techniques to isolate these exosomes from body fluids, our overall objective for this application is to test the association between maternal adipocyte-derived exosomes and infant adiposity while building upon existing research capacity for a prospective multicenter study in India. We will achieve this objective by using clinical data and biospecimens from Indian maternal-infant pairs that are part of a longitudinal cohort study (current n=288) led at King Edward Memorial Hospital, Pune, India. The US-Indian team generated preliminary data for this application during a recent visit by the PI to India. Our central hypothesis is that reduced levels of maternal and cord blood adipocyte-derived exosomal microRNAs that target adipogenesis are associated with high infant adiposity. Indeed, our preliminary data support that maternal adiposity/obesity suppresses microRNAs that target adipogenesis pathway members and therefore are predicted to result in increased fetal adipogenesis. The research team is comprised of NIH- and Indian-funded investigators with international expertise in all relevant fields. The richness of the cohort biorepository is a major asset to this evolving collaboration. The study matches well with the goals indicated by the PAR-16-052 - Global Noncommunicable Diseases and Injury across the Lifespan: Exploratory Research (R21): “Support locally-relevant and catalytic pilot research”; and “Support development of diagnostics, prevention, treatment and implementation strategies.” Our long-term goal is to transform current thinking about the pathogenesis of childhood adiposity and cardiometabolic diseases. Moreover, the project is likely to identify potential therapeutic targets for the primary prevention of these diseases in India and the United States, laying the foundation for more a comprehensive research program that enriches the knowledge base and leads to additional research proposals to the NIH and other funders from this US and Indian team.