Rosiglitazone ameliorates insulin resistance in brown adipocytes of Wistar rats by impairing TNF-alpha induction of p38 and p42/p44 mitogen-activated protein kinases

R Hernandez, T Teruel, C de Alvaro, M Lorenzo
Diabetologia 2004, 47 (9): 1615-24

AIMS/HYPOTHESIS: TNF-alpha caused insulin resistance on glucose uptake and on insulin signalling in fetal brown adipocytes. Since treatment with TNF-alpha activates stress kinases, including c-jun NH2 terminal kinase (JNK), and p42/p44 and p38 mitogen-activated protein kinases (MAPK), we explored the contribution of these pathways to insulin resistance by TNF-alpha. Rosiglitazone is used to treat Type 2 diabetes as it improves insulin sensitivity in vivo. However, its ability to ameliorate TNF-alpha-induced insulin resistance in brown adipocytes remains to be explored.

METHODS: We used fetal rat primary brown adipocytes cultured with TNF-alpha, with or without stress kinase inhibitors or rosiglitazone, and further stimulated with insulin. Then, we measured glucose uptake and GLUT4 translocation. To determine the insulin signalling cascade, we submitted cells to lysis, immunoprecipitation and immunoblotting.

RESULTS: Exposure to TNF-alpha for 24 h impairs insulin stimulation of the phosphatidylinositol (PI) 3-kinase activity associated with IRS-2 and Akt activity. Pretreatment with PD98059 or PD169316, which inhibit p42/p44MAPK and p38MAPK respectively, restored insulin signalling and insulin-induced glucose uptake in the presence of TNF-alpha. However, in the presence of SP600125, an inhibitor of JNK, TNF-alpha still produced insulin resistance. Rosiglitazone ameliorated insulin resistance by TNF-alpha in brown adipocytes, restoring completely insulin-stimulated glucose uptake and insulin-induced GLUT4 translocation to plasma membrane in parallel to the insulin signalling cascade IRS-2/PI 3-kinase/Akt.

CONCLUSIONS/INTERPRETATION: Rosiglitazone treatment impaired TNF-alpha activation of p38 and p42/p44MAPK, restoring insulin signalling and leading to normalisation of glucose uptake.

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