Stimulation of exosome biogenesis by adiponectin, a circulating factor secreted from adipocytes

Adiponectin is an adipocyte-derived circulating factor that protects various organs and tissues. Such a pleiotropic action mechanism has not yet been fully explained. Clinically important multimer adiponectin existing in serum bound to cells expressing T-cadherin, a glycosylphosphatidylinositol-anchored cadherin, but not to the cells expressing other known receptors, AdipoRs or calreticulin. Adiponectin bound to the cell-surface, accumulated inside of multivesicular bodies through T-cadherin, and increased exosome biogenesis and secretion from the cells. Such increased exosome production accompanied the reduction of cellular ceramides in endothelial cells and mouse aorta, and enhanced skeletal muscle regeneration. Significantly lower plasma exosome levels were found in mice genetically deficient in either adiponectin or T-cadherin. Therapeutic effects of mesenchymal stem cells (MSCs) for a pressure overload-induced heart failure in mice required the presence of adiponectin in plasma, T-cadherin expression and exosome biogenesis in MSCs themselves, accompanying an increase of plasma exosomes. Essentially all organs seem to have MSCs and/or their related somatic stem cells expressing T-cadherin. Our recent studies suggested the importance of exosome-stimulation by multimer adiponectin in its well-known pleiotropic organ protections.