Modulation of the JNK pathway in liver affects insulin resistance status.
The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes.
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Yoshihisa
Y
Nakatani
Hideaki
H
Kaneto
Dan
D
Kawamori
Masahiro
M
Hatazaki
Takeshi
T
Miyatsuka
Taka-Aki
TA
Matsuoka
Yoshitaka
Y
Kajimoto
Munehide
M
Matsuhisa
Yoshimitsu
Y
Yamasaki
Masatsugu
M
Hori
D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005951:Glucose Tolerance Test; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D013395:Sucrose / Q000008:administration & dosage
D004041:Dietary Fats; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D013395:Sucrose; D048031:JNK Mitogen-Activated Protein Kinases