Hypoglycentic action of thiazolidinediones/peroxisome proliferator-activated receptor γ by inhibition of the c-Jun NH2-terminal kinase pathway

Type 2 diabetes results from progressive pancreatic P-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) gamma synthetic ligands thiazolidinediones (TZDs) enhance insulin sensitivity. Here, we show that the TZD)s rosiglitazone and troglitazone inhibit tumor necrosis factor-alpha-induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPAR gamma mediates this inhibitory action because 1) it is reproduced by other chemically unrelated PPAR gamma agonist ligands and blocked by PPAR gamma antagonists; 2) it is enhanced by PPAR gamma overexpression; and 3) it is abrogated by PPAR gamma RNA interference. In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic beta-cells exposed to interleukin-1 beta. 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 P-cell protective actions of TZDs/PPAR gamma.