Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes

• Published in: American journal of physiology: endocrinology and metabolism 2012-02, Vol.302 (3), p.E286-E296
• Main Authors: Iwashita, Misaki, Sakoda, Hideyuki, Kushiyama, Akifumi, Fujishiro, Midori, Ohno, Haruya, Nakatsu, Yusuke, Fukushima, Toshiaki, Kumamoto, Sonoko, Tsuchiya, Yoshihiro, Kikuchi, Takako, Kurihara, Hiroki, Akazawa, Hiroshi, Komuro, Issei, Kamata, Hideaki, Nishimura, Fusanori, Asano, Tomoichiro
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes, White - drug effects; Adipocytes, White - immunology; Adipocytes, White - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Cells, Cultured; Coculture Techniques; Humans; Insulin Resistance; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR gamma - antagonists & inhibitors; PPAR gamma - metabolism; Receptor, Angiotensin, Type 1 - chemistry; Receptor, Angiotensin, Type 1 - genetics; Receptor, Angiotensin, Type 1 - metabolism; RNA Interference; RNA, Small Interfering; Tetrazoles - pharmacology; Valine - analogs & derivatives; Valine - pharmacology; Valsartan
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00324.2011

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 NH(2)-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.