Serum Exosomal Proteins—A New Component of Intercellular Communication in Metabolism

Adipose tissue is an important endocrine organ; both excess or deficiency of adipose is associated with metabolic syndrome. MicroRNAs (miRNAs) play a fundamental role in regulating adipocyte function and metabolism. Recently, we showed that a large fraction of circulating miRNAs comes from exosomes released by adipose tissue and that mice with an adipose-specific knockout of the miRNA-processing enzyme Dicer (ADicerKO) exhibit lipodystrophy and metabolic syndrome. This is due, in part, to a loss of multiple circulating exosomal microRNAs and their effects on gene expression in liver and other tissues. In this study, we explored the role of exosomal proteins in metabolism by comparing the serum exosomal proteome of wild type (WT) and AdicerKO mice. To this end, we isolated serum exosomes from WT and KO mice and performed quantitative proteomics by LC-MS. A total of 277 exosomal proteins were identified, of which 12 were significantly downregulated and 16 were upregulated by ≥1.5 in AdicerKO mice. Among these were two important adipokines. Thus, the insulin sensitizer adiponectin was downregulated in exosomes, while the insulin resistance-associated adipokine retinol-binding protein-4 (Rbp4) was upregulated. Transthyretin, which binds to and extends Rbp4 half-life, was also increased in serum exosomes from AdicerKO mice. Additionally, serum amyloids A-1 and A-4, serum amyloid component P, haptoglobin and ceruloplasmin, which are adipose and/or liver-specific in origin and often altered in insulin resistant states, were down-regulated in the exosomes of knockout mice.

In summary, serum exosomes contain multiple proteins which can modulate insulin sensitivity or insulin resistance. Induction of lipodystrophy by KO of Dicer in adipose markedly alters the circulating exosomal proteome due to loss of fat or the secondary hepatosteatosis this produces. These exosomal proteins provide potential new signals in the crosstalk between fat, liver and other tissues in response to metabolic disease.