title: Valsartan, independently of AT1 receptor or PPARγ, suppresses LPS-induced macrophage activation and improves insulin resistance in cocultured adipocytes.
abstract: 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.
authors: Department of Biomedical Chemistry, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors: Misaki
authors: M
authors: Iwashita
authors: Hideyuki
authors: H
authors: Sakoda
authors: Akifumi
authors: A
authors: Kushiyama
authors: Midori
authors: M
authors: Fujishiro
authors: Haruya
authors: H
authors: Ohno
authors: Yusuke
authors: Y
authors: Nakatsu
authors: Toshiaki
authors: T
authors: Fukushima
authors: Sonoko
authors: S
authors: Kumamoto
authors: Yoshihiro
authors: Y
authors: Tsuchiya
authors: Takako
authors: T
authors: Kikuchi
authors: Hiroki
authors: H
authors: Kurihara
authors: Hiroshi
authors: H
authors: Akazawa
authors: Issei
authors: I
authors: Komuro
authors: Hideaki
authors: H
authors: Kamata
authors: Fusanori
authors: F
authors: Nishimura
authors: Tomoichiro
authors: T
authors: Asano
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007333:Insulin Resistance; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D000894:Anti-Inflammatory Agents, Non-Steroidal; D047495:PPAR gamma; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068756:Valsartan; D014633:Valine