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Hypoglycemic action of thiazolidinediones/peroxisome proliferator-activated receptor by inhibition of the c-Jun N-terminal kinase pathway

¹Institute for Research in Biomedicine (IRB), Scientific Park of Barcelona, and Department of Biochemistry and Molecular Biology (Pharmacy), University of Barcelona, Barcelona, Spain

Correspondence: ccaelles{at}pcb.ub.es

Type 2 diabetes mellitus results from progressive pancreatic ß-cell dysfunction caused by chronic insulin resistance. Activation of c-Jun N-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 (TNF)--induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPAR mediates this inhibitory action since a) it is reproduced by other chemically unrelated PPAR agonist ligands and blocked by PPAR antagonists; b) it is enhanced by PPAR overexpression; and c) it is abrogated by PPAR RNA interference (RNAi). In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic ß-cells exposed to interleukin (IL)-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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