Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells

Obesity (Silver Spring). 2014 Oct;22(10):2216-23. doi: 10.1002/oby.20847. Epub 2014 Jul 17.


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.

Keywords: adipose tissue; extracellular vesicles; insulin resistance; liver; muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / ultrastructure*
  • Aged
  • Animals
  • Cell-Derived Microparticles / physiology
  • Cells, Cultured
  • Exosomes / physiology*
  • Female
  • HEK293 Cells
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Insulin / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Middle Aged
  • Muscle Cells / metabolism*
  • NIH 3T3 Cells
  • Signal Transduction / drug effects


  • Insulin