Abstract

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