Adipose Tissue Exosomal Proteomic Profile Reveals a Role on Placenta Glucose Metabolism in Gestational Diabetes Mellitus

Abstract Context Molecules produced by adipose tissue (AT) function as an endocrine link between maternal AT and fetal growth by regulating placental function in normal women and women with gestational diabetes mellitus (GDM). Objective We hypothesized that AT-derived exosomes (exo-AT) from women with GDM would carry a specific set of proteins that influences glucose metabolism in the placenta. Design Exosomes were isolated from omental AT-conditioned media from normal glucose tolerant (NGT) pregnant women (n = 65) and pregnant women with GDM (n = 82). Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry was used to construct a small ion library from AT and exosomal proteins, followed by ingenuity pathway analysis to determine the canonical pathways and biofunctions. The effect of exosomes on human placental cells was determined using a Human Glucose Metabolism RT2 Profiler PCR array. Results The number of exosomes (vesicles/μg of tissue/24 hours) was substantially (1.7-fold) greater in GDM than in NGT, and the number of exosomes correlated positively with the birthweight Z score. Ingenuity pathway analysis of the exosomal proteins revealed differential expression of the proteins targeting the sirtuin signaling pathway, oxidative phosphorylation, and mechanistic target of rapamycin signaling pathway in GDM compared with NGT. GDM exo-AT increased the expression of genes associated with glycolysis and gluconeogenesis in placental cells compared with the effect of NGT exo-AT. Conclusions Our findings are consistent with the possibility that AT exosomes play an important role in mediating the changes in placental function in GDM and might be responsible for some of the adverse consequences in this pregnancy complication, such as fetal overgrowth. A specific set of proteins were selectively enriched in exosomes compared with their originating AT in GDM, which were then associated with changes in glucose metabolism in placental cells.