title: Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells.
abstract: OBJECTIVE
  Insulin resistance (IR) is a key mechanism in obesity-induced cardiovascular disease. To unravel mechanisms whereby human adipose tissue (AT) contributes to systemic IR, the effect of human AT-extracellular vesicles (EVs) on insulin signaling in liver and muscle cells was determined.
  
  
  METHODS
  EVs released from human subcutaneous (SAT) and omental AT (OAT)-explants ex vivo were used for stimulation of hepatocytes and myotubes in vitro. Subsequently, insulin-induced Akt phosphorylation and expression of gluconeogenic genes (G6P, PEPCK) was determined. AT-EV adipokine levels were measured by multiplex immunoassay, and AT-EVs were quantified by high-resolution flow cytometry.
  
  
  RESULTS
  In hepatocytes, AT-EVs from the majority of patients inhibited insulin-induced Akt phosphorylation, while EVs from some patients stimulated insulin-induced Akt phosphorylation. In myotubes AT-EVs exerted an ambiguous effect on insulin signaling. Hepatic Akt phosphorylation related negatively to G6P-expression by both SAT-EVs (r = -0.60, P = 0.01) and OAT-EVs (r = -0.74, P = 0.001). MCP-1, IL-6, and MIF concentrations were higher in OAT-EVs compared to SAT-EVs and differently related to lower Akt phosphorylation in hepatocytes. Finally, the number of OAT-EVs correlated positively with liver enzymes indicative for liver dysfunction.
  
  
  CONCLUSIONS
  Human AT-EVs can stimulate or inhibit insulin signaling in hepatocytes- possibly depending on their adipokine content- and may thereby contribute to systemic IR.
authors.affiliation: Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands; Molecular Cancer Research, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: Mariëtte E G
authors.initials: ME
authors.lastname: Kranendonk
authors.forename: Frank L J
authors.initials: FL
authors.lastname: Visseren
authors.forename: Joost A
authors.initials: JA
authors.lastname: van Herwaarden
authors.forename: Esther N M
authors.initials: EN
authors.lastname: Nolte-'t Hoen
authors.forename: Wilco
authors.initials: W
authors.lastname: de Jager
authors.forename: Marca H M
authors.initials: MH
authors.lastname: Wauben
authors.forename: Eric
authors.initials: E
authors.lastname: Kalkhoven
mesh_terms: D000273:Adipose Tissue / Q000648:ultrastructure*; D000368:Aged; D000818:Animals; D055252:Cell-Derived Microparticles / Q000502:physiology; D002478:Cells, Cultured; D055354:Exosomes / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D032342:Muscle Cells / Q000378:metabolism*; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007328:Insulin
keywords: adipose tissue; extracellular vesicles; insulin resistance; liver; muscle