Hypoglycemic action of thiazolidinediones/peroxisome proliferator-activated receptor gamma by inhibition of the c-Jun NH2-terminal kinase pathway.
Type 2 diabetes results from progressive pancreatic beta-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 TZDs rosiglitazone and troglitazone inhibit tumor necrosis factor-alpha-induced JNK activation in 3T3-L1 adipocytes. Our results indicate that PPARgamma mediates this inhibitory action because 1) it is reproduced by other chemically unrelated PPARgamma agonist ligands and blocked by PPARgamma antagonists; 2) it is enhanced by PPARgamma overexpression; and 3) it is abrogated by PPARgamma RNA interference. In addition, we show that rosiglitazone inhibits JNK activation and promotes the survival of pancreatic beta-cells exposed to interleukin-1beta. 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 beta-cell protective actions of TZDs/PPARgamma.
Díaz-Delfín
Julieta
J
Institute for Research in Biomedicine, Scientific Park of Barcelona, E-08028-Barcelona, Spain.
Morales
Mònica
M
Caelles
Carme
C
D017667:Adipocytes / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D048031:JNK Mitogen-Activated Protein Kinases; D000077288:Troglitazone