Activated Kupffer cells inhibit insulin sensitivity in obese mice
| Autor: | Pranitha Vangala, Karen Gallagher-Dorval, Sarah M. Nicoloro, Yuefei Shen, Joseph C. Yawe, Jessica Cohen, Richard A. Perugini, Michaela Tencerova, Olga T. Gupta, David J. Pedersen, Lorena Garcia-Menendez, Michael P. Czech, Myriam Aouadi |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Small interfering RNA Kupffer Cells Mice Obese Inflammation In Vitro Techniques Biology Systemic inflammation Biochemistry Research Communication Mice Drug Delivery Systems Insulin resistance Internal medicine Genetics medicine Animals Humans Gene silencing Gene Silencing Obesity RNA Small Interfering Molecular Biology Glucose tolerance test medicine.diagnostic_test Fatty liver Transcription Factor RelA Glucose Tolerance Test Lipid Metabolism medicine.disease Fatty Liver Mice Inbred C57BL Endocrinology Injections Intravenous Cytokines Cytokine secretion Insulin Resistance medicine.symptom Biotechnology |
| Zdroj: | The FASEB Journal. 29:2959-2969 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | Obesity promotes insulin resistance associated with liver inflammation, elevated glucose production, and type 2 diabetes. Although insulin resistance is attenuated in genetic mouse models that suppress systemic inflammation, it is not clear whether local resident macrophages in liver, denoted Kupffer cells (KCs), directly contribute to this syndrome. We addressed this question by selectively silencing the expression of the master regulator of inflammation, NF-κB, in KCs in obese mice. We used glucan-encapsulated small interfering RNA particles (GeRPs) that selectively silence gene expression in macrophages in vivo. Following intravenous injections, GeRPs containing siRNA against p65 of the NF-κB complex caused loss of NF-κB p65 expression in KCs without disrupting NF-κB in hepatocytes or macrophages in other tissues. Silencing of NF-κB expression in KCs in obese mice decreased cytokine secretion and improved insulin sensitivity and glucose tolerance without affecting hepatic lipid accumulation. Importantly, GeRPs had no detectable toxic effect. Thus, KCs are key contributors to hepatic insulin resistance in obesity and a potential therapeutic target for metabolic disease.—Tencerova, M., Aouadi, M., Vangala, P., Nicoloro, S. M., Yawe, J. C., Cohen, J. L., Shen, Y., Garcia-Menendez, L., Pedersen, D. J., Gallagher-Dorval, K., Perugini, R. A., Gupta, O. T., Czech, M. P. Activated Kupffer cells inhibit insulin sensitivity in obese mice. |
| Databáze: | OpenAIRE |
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