Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice
| Autor: | Ruojing Yang, Sevan Brodjian, Martin J. Voorbach, Terry K. Surowy, Katherine T. Landschulz, Christine A. Collins, Stella Doktor, Denise Wilcox, Cristina M. Rondinone, James M. Trevillyan, Peer B. Jacobson, Eugene N. Bush, Emily Lin, Phong Nguyen, Deanna L. Haasch, Paul M. Jung |
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| Rok vydání: | 2007 |
| Předmět: |
endocrine system
medicine.medical_specialty medicine.medical_treatment Mice Obese Carbohydrate metabolism Biology environment and public health Biochemistry Gene Expression Regulation Enzymologic Adenoviridae Mice Insulin resistance Internal medicine Coactivator medicine Animals Insulin Mitogen-Activated Protein Kinase 8 Phosphorylation Molecular Biology Triglycerides DNA Primers Gene knockdown Glucokinase Cell Biology medicine.disease Animal Feed Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha PPAR gamma enzymes and coenzymes (carbohydrates) Insulin receptor Endocrinology Glucose Liver biology.protein Trans-Activators biological phenomena cell phenomena and immunity Diet-induced obese hormones hormone substitutes and hormone antagonists Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 282(31) |
| ISSN: | 0021-9258 |
| Popis: | The c-Jun N-terminal kinases (JNKs) have been implicated in the development of insulin resistance, diabetes, and obesity. Genetic disruption of JNK1, but not JNK2, improves insulin sensitivity in diet-induced obese (DIO) mice. We applied RNA interference to investigate the specific role of hepatic JNK1 in contributing to insulin resistance in DIO mice. Adenovirus-mediated delivery of JNK1 short-hairpin RNA (Ad-shJNK1) resulted in almost complete knockdown of hepatic JNK1 protein without affecting JNK1 protein in other tissues. Liver-specific knockdown of JNK1 resulted in significant reductions in circulating insulin and glucose levels, by 57 and 16%, respectively. At the molecular level, JNK1 knockdown mice had sustained and significant increase of hepatic Akt phosphorylation. Furthermore, knockdown of JNK1 enhanced insulin signaling in vitro. Unexpectedly, plasma triglyceride levels were robustly elevated upon hepatic JNK1 knockdown. Concomitantly, expression of proliferator-activated receptor gamma coactivator 1 beta, glucokinase, and microsomal triacylglycerol transfer protein was increased. Further gene expression analysis demonstrated that knockdown of JNK1 up-regulates the hepatic expression of clusters of genes in glycolysis and several genes in triglyceride synthesis pathways. Our results demonstrate that liver-specific knockdown of JNK1 lowers circulating glucose and insulin levels but increases triglyceride levels in DIO mice. |
| Databáze: | OpenAIRE |
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