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Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells
Author(s) -
Kranendonk Mariëtte E.G.,
Visseren Frank L.J.,
Herwaarden Joost A.,
Nolte't Hoen Esther N.M.,
Jager Wilco,
Wauben Marca H.M.,
Kalkhoven Eric
Publication year - 2014
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.20847
Subject(s) - protein kinase b , phosphorylation , insulin , insulin receptor , medicine , adipokine , endocrinology , adipose tissue , insulin resistance , microbiology and biotechnology , chemistry , biology
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.