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)，也是世界上 低出生体重儿(LBW)数量最多(每年600-800万)。乍一看，这些可能看起来 不相干的。然而，出生体重与成年后患糖尿病的最终风险之间的联系通常是 被描述为“U形”(即低出生体重和高出生体重都会增加个人患成人糖尿病的风险)。 与直觉相反的是，印度LBW婴儿出生时肥胖率(即体脂百分比)很高--即所谓的“瘦脂肪” “印度悖论”。这归因于影响胎儿大小和身体成分的多种因素，包括 母亲的表型为瘦脂肪、营养不良和血糖升高。这些低出生体重儿患上 成人肥胖和心脏代谢性疾病的发展。代际和早期生命(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，与肥胖相关的母亲 该因子通过胎盘对胎儿心脏代谢的发育途径进行重新编程。PIS团队最近 脂肪细胞来源的外切体被确认为能够驱动胎儿心脏代谢异常的母性因素 肥胖儿童心脏代谢性疾病的发育和已知的器官间介质 成年人。作为纳米颗粒大小的内吞囊泡，这些外切体可以穿过胎盘和它们的microrna。 据预测，这些内容会改变发育途径基因的表达。因为我们开发了一些技术来 从体液中分离这些外切体，我们这项应用的总体目标是测试这种联系 在现有研究的基础上，母亲脂肪细胞来源的外切体与婴儿肥胖之间的关系 在印度进行预期多中心研究的能力。我们将通过使用临床数据和 来自印度母婴配对的生物寄生虫是纵向队列研究的一部分(目前n=288) 在印度浦那的爱德华国王纪念医院。美国-印度团队为此生成了初步数据 在国际刑警组织最近访问印度期间提出的申请。我们的中心假设是，降低的母体水平和 以脂肪生成为靶点的脐血脂肪细胞来源的外体microRNAs与高婴儿有关 肥胖症。事实上，我们的初步数据支持，母亲肥胖/肥胖抑制了 靶向脂肪生成途径成员，因此预测会导致胎儿脂肪生成增加。 研究团队由美国国立卫生研究院和印度资助的具有国际专业知识的研究人员组成 相关字段。队列生物信息库的丰富是这一不断发展的合作的一项主要资产。这个 研究与PAR-16-052-全球非传染性疾病和 整个生命周期的伤害：探索性研究(R21)：“支持与当地相关和具有催化作用的先导研究”； 以及“支持诊断、预防、治疗和实施战略的发展”。我们的长期合作 目标是改变目前对儿童肥胖和心脏代谢性疾病发病机制的看法 疾病。此外，该项目可能确定初级预防的潜在治疗目标。 这些疾病在印度和美国，为更全面的研究奠定了基础 该计划丰富了知识库，并向NIH和其他机构提出了其他研究建议 来自美国和印度团队的资助者。

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.