Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB
| Autor: | Lone Hansen, Daniel Frantz, Dongsheng Cai, Peter A. Melendez, Steven E. Shoelson, Minsheng Yuan, Jongsoon Lee |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Genetically modified mouse
Male medicine.medical_specialty medicine.medical_treatment Inflammation Mice Transgenic IκB kinase Biology Protein Serine-Threonine Kinases General Biochemistry Genetics and Molecular Biology Article Proinflammatory cytokine chemistry.chemical_compound Mice Insulin resistance Internal medicine medicine Animals Humans Insulin Obesity Interleukin-6 Macrophages Anti-Inflammatory Agents Non-Steroidal NF-kappa B NF-κB General Medicine medicine.disease Dietary Fats Salicylates I-kappa B Kinase Rats Mice Inbred C57BL IκBα Endocrinology Cytokine chemistry Hepatocytes Carbohydrate Metabolism Cytokines Female medicine.symptom Insulin Resistance Signal Transduction |
| Popis: | We show that NF-kappaB and transcriptional targets are activated in liver by obesity and high-fat diet (HFD). We have matched this state of chronic, subacute 'inflammation' by low-level activation of NF-kappaB in the liver of transgenic mice, designated LIKK, by selectively expressing constitutively active IKK-b in hepatocytes. These mice exhibit a type 2 diabetes phenotype, characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. The hepatic production of proinflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, was increased in LIKK mice to a similar extent as induced by HFD in in wild-type mice. Parallel increases were observed in cytokine signaling in liver and mucscle of LIKK mice. Insulin resistance was improved by systemic neutralization of IL-6 or salicylate inhibition of IKK-beta. Hepatic expression of the IkappaBalpha superrepressor (LISR) reversed the phenotype of both LIKK mice and wild-type mice fed an HFD. These findings indicate that lipid accumulation in the liver leads to subacute hepatic 'inflammation' through NF-kappaB activation and downstream cytokine production. This causes insulin resistance both locally in liver and systemically. |
| Databáze: | OpenAIRE |
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