Pharmacological characterization of a small molecule inhibitor of c-Jun kinase
| Autor: | Karen Siegel, Helen Kim Cho, David Looper, Shawn C Black, Xiao-Hong Yu, Scott Rp McDonnell, Dawn Kelly-Sullivan, Sergei Timofeevski, Junming Yie, Celia P. Briscoe, Kathleen M. Ogilvie, Ping Chen, Manli Shi, James S. Fraser |
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| Rok vydání: | 2008 |
| Předmět: |
Blood Glucose
Lipopolysaccharides Male medicine.medical_specialty Proto-Oncogene Proteins c-jun Physiology Ratón Adipose Tissue White Endocrinology Diabetes and Metabolism medicine.medical_treatment Aminopyridines Biology Eating Mice Insulin resistance 3T3-L1 Cells Physiology (medical) Internal medicine medicine Animals Humans Insulin Mitogen-Activated Protein Kinase 8 Obesity Phosphorylation Protein Kinase Inhibitors U937 cell Tumor Necrosis Factor-alpha Kinase Body Weight c-jun JNK Mitogen-Activated Protein Kinases U937 Cells medicine.disease Dietary Fats Small molecule Mice Inbred C57BL Endocrinology Insulin Receptor Substrate Proteins Cytokines Insulin Resistance Immediate early gene |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 295:E1142-E1151 |
| ISSN: | 1522-1555 0193-1849 |
| Popis: | c-Jun NH2-terminal kinase (JNK) plays an important role in insulin resistance; however, identification of pharmacologically potent and selective small molecule JNK inhibitors has been limited. Compound A has a cell IC50 of 102 nM and is at least 100-fold selective against related kinases and 27-fold selective against glycogen synthase kinase-3β and cyclin-dependent kinase-2. In C57BL/6 mice, compound A reduced LPS-mediated increases in both plasma cytokine levels and phosphorylated c-Jun in adipose tissue. Treatment of mice fed a high-fat diet with compound A for 3 wk resulted in a 13.1 ± 1% decrease in body weight and a 9.3 ± 1.5% decrease in body fat, compared with a 6.6 ± 2.1% increase in body weight and a 6.7 ± 2.1% increase in body fat in vehicle-treated mice. Mice pair fed to those that received compound A exhibited a body weight decrease of 7 ± 1% and a decrease in body fat of 1.6 ± 1.3%, suggesting that reductions in food intake could not account solely for the reductions in adiposity observed. Compound A dosed at 30 mg/kg for 13 days in high-fat fed mice resulted in a significant decrease in phosphorylated c-Jun in adipose tissue accompanied by a decrease in weight and reductions in glucose and triglycerides and increases in insulin sensitivity to levels comparable with those in lean control mice. The ability of compound A to reduce the insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) von Ser307 and partially reverse the free fatty acid inhibition of glucose uptake in 3T3L1 adipocytes, suggests that enhancement of insulin signaling in addition to weight loss may contribute to the effects of compound A on insulin sensitization in vivo. Pharmacological inhibition of JNK using compound A may therefore offer an effective therapy for type 2 diabetes mediated at least in part via weight reduction. |
| Databáze: | OpenAIRE |
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