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Previous studies suggest that adipocyte-derived exosomes play a role in cell-to-cell communication during the development of metabolic diseases. However, the characteristics and function of exosomes released from adipocytes in vivo remain to be elucidated. Clearly, exosomes released from adipocytes could exist in the circulation. In addition, because the composition of exosomes is heterogenic, depending on the cellular origin of the exosome, adipocyte-derived exosomes could be accompanied by molecules produced specifically in adipocytes. In this context, this study postulated that such molecules associated with exosomes in the serum could be markers for adipocyte-derived exosomes in vivo. This study particularly focused on secretory proteins produced specifically in adipocytes, namely adipocytokines including adiponectin, leptin, and resistin. Serum adiponectin is partially associated with exosomesBased on western blotting, CD63, a well-known protein marker of exosomes, was concentrated in the pellet of mouse serum after ultracentrifugation, suggesting successful isolation of exosomes. Western blotting detected adiponectin but no leptin and only trace amounts of resistin in the exosome fraction. After ultracentrifugation on a discontinuous gradient, both adiponectin and CD63 were detected in a fraction at a density of 1.17 g/mL, consistent with the density of exosomes. The adiponectin signal in the exosome fraction was decreased by proteinase K treatment and completely quenched by a combination of proteinase K and Triton X-100. These results suggest that a portion of adiponectin exists as a transmembrane protein in the exosomes in mouse serum. showed that the concentration of adiponectin in the serum and the ratio of adiponectin to total protein in the exosome fraction were lower in obese mice than in lean mice.In conclusion, this study showed that serum adiponectin is partially associated with exosomes in mice. Considering that adiponectin is produced exclusively by adipocytes, adiponectin-associated exosomes in serum could be derived from adipocytes. This study proposes that adiponectin could be a marker for exosomes released from adipocytes in vivo.iii

The microbiota-gut-brain axis plays an important role in the development of stress-induced mental disorders. We previously established the subchronic and mild social defeat stress (sCSDS) model, a murine experimental model of depression, and investigated the metabolomic profiles of plasma and liver. Here we used omics approaches to identify stress-induced changes in the gastrointestinal tract. Mice exposed to sCSDS for 10 days showed the following changes: (1) elevation of cholic acid and reduction of 5-aminovaleric acid among cecal metabolites; (2) downregulation of genes involved in the immune response in the terminal ileum; (3) a shift in the diversity of the microbiota in cecal contents and feces; and (4) fluctuations in the concentrations of cecal metabolites produced by gut microbiota reflected in plasma and hepatic metabolites. Operational taxonomic units within the family Lachnospiraceae showed an inverse correlation with certain metabolites. The social interaction score correlated with cecal metabolites, IgA, and cecal and fecal microbiota, suggesting that sCSDS suppressed the ileal immune response, altering the balance of microbiota, which together with host cells and host enzymes resulted in a pattern of accumulated metabolites in the intestinal ecosystem distinct from that of control mice.