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

摘要

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.