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Hypoglycemic Action of Thiazolidinediones/Peroxisome Proliferator–Activated Receptor by Inhibition of the c-Jun NH₂-Terminal Kinase Pathway

From the Institute for Research in Biomedicine, Scientific Park of Barcelona, and the Department of Biochemistry and Molecular Biology (Pharmacy), University of Barcelona, Barcelona, Spain

Address correspondence and reprint requests to Carme Caelles, Institute for Research in Biomedicine, Scientific Park of Barcelona, Josep Samitier, 1-5, E-08028-Barcelona, Spain. E-mail: ccaelles{at}pcb.ub.es

Abbreviations: AUC, area under curve; BADGE, bisphenol A diglycidyl ether; 2-DG, 2-deoxy-D-[³H]glucose; DMEM, Dulbecco's modified Eagle's medium; 15d-PGJ₂, 15-deoxy-^12,14-prostaglandin J₂; FFA, free fatty acid; F-L-Leu, N(9-fluorenylmethylloxycarbonyl) leucine derivative, FMOC-L-Leucine; GTT, glucose tolerance test; JNK, c-Jun NH₂-terminal kinase; IRS-1, insulin receptor substrate-1; IL, interleukin; MAPK, mitogen-activated protein kinase; PPAR, peroxisome proliferator–activated receptor; RNAi, RNA interference; TNF-, tumor necrosis factor-; TZD, thiazolidinedione

Type 2 diabetes results from progressive pancreatic ß-cell dysfunction caused by chronic insulin resistance. Activation of c-Jun NH₂-terminal kinase (JNK) inhibits insulin signaling in cultured cells and in vivo and thereby promotes insulin resistance. Conversely, the peroxisome proliferator–activated receptor (PPAR) synthetic ligands thiazolidinediones (TZDs) enhance insulin sensitivity. Here, we show that the TZDs rosiglitazone and troglitazone inhibit tumor necrosis factor-–induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPAR mediates this inhibitory action because 1) it is reproduced by other chemically unrelated PPAR agonist ligands and blocked by PPAR antagonists; 2) it is enhanced by PPAR overexpression; and 3) it is abrogated by PPAR RNA interference. In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic ß-cells exposed to interleukin-1ß. In vivo, the abnormally elevated JNK activity is inhibited in peripheral tissues by rosiglitazone in two distinct murine models of obesity. Moreover, rosiglitazone fails to enhance insulin-induced glucose uptake in primary adipocytes from ob/ob JNK1^–/– mice. Accordingly, we demonstrate that the hypoglycemic action of rosiglitazone is abrogated in the diet-induced obese JNK1-deficient mice. In summary, we describe a novel mechanism based on targeting the JNK signaling pathway, which is involved in the hypoglycemic and potentially in the pancreatic ß-cell protective actions of TZDs/PPAR.

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