Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes
| Autor: | Iwashita, M., Sakoda, H., Kushiyama, A., Fujishiro, M., Ohno, H., Nakatsu, Y., Fukushima, Toshiaki, Kumamoto, S., Tsuchiya, Y., Kikuchi, T., Kurihara, H., Akazawa, H., Komuro, I., Kamata, H., Nishimura, F., Asano, T. |
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| Rok vydání: | 2012 |
| Předmět: |
Lipopolysaccharide
Physiology Anti-Inflammatory Agents Non-Steroidal/*pharmacology Endocrinology Diabetes and Metabolism Adipocytes White Tetrazoles Adipose tissue Tetrazoles/*pharmacology Mice chemistry.chemical_compound Adipocyte Macrophage Valine/*analogs & derivatives/pharmacology RNA Small Interfering Cells Cultured Mice Knockout Anti-Inflammatory Agents Non-Steroidal Valine PPAR gamma/antagonists & inhibitors/*metabolism Receptor Angiotensin Type 1/chemistry/genetics/*metabolism Valsartan RNA Interference medicine.symptom medicine.medical_specialty Adipocytes White/*drug effects/immunology/metabolism Inflammation Receptor Angiotensin Type 1 Cell Line Insulin resistance 3T3-L1 Cells Angiotensin II Type 1 Receptor Blockers/pharmacology Physiology (medical) Internal medicine medicine Animals Humans Macrophages/drug effects/immunology/metabolism Angiotensin II receptor type 1 Macrophages Macrophage Activation/*drug effects Macrophage Activation Insulin Resistance medicine.disease Angiotensin II Coculture Techniques PPAR gamma Mice Inbred C57BL Endocrinology chemistry Angiotensin II Type 1 Receptor Blockers |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 302:E286-E296 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00324.2011 |
| Popis: | Macrophages are integrated into adipose tissues and interact with adipocytes in obese subjects, thereby exacerbating adipose insulin resistance. This study aimed to elucidate the molecular mechanism underlying the insulin-sensitizing effect of the angiotensin II receptor blocker (ARB) valsartan, as demonstrated in clinical studies. Insulin signaling, i.e., insulin receptor substrate-1 and Akt phosphorylations, in 3T3-L1 adipocytes was impaired markedly by treatment with tumor necrosis factor-α (TNFα) or in the culture medium of lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophages, and valsartan had no effects on these impairments. However, in contrast, when cocultured with RAW 264.7 cells using a transwell system, the LPS-induced insulin signaling impairment in 3T3-L1 adipocytes showed almost complete normalization with coaddition of valsartan. Furthermore, valsartan strongly suppressed LPS-induced productions of cytokines such as interleukin (IL)-1β, IL-6, and TNFα with nuclear factor-κB activation and c-Jun NH2-terminal kinase phosphorylation in RAW 264.7 and primary murine macrophages. Very interestingly, this effect of valsartan was also observed in THP-1 cells treated with angiotensin II type 1 (AT1) siRNA or a peroxisome proliferator-activated receptor-γ (PPARγ) antagonist as well as macrophages from AT1a receptor-knockout mice. We conclude that valsartan suppresses the inflammatory response of macrophages, albeit not via PPARγ or the AT1a receptor. This suppression appears to secondarily improve adipose insulin resistance. |
| Databáze: | OpenAIRE |
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