Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet[S]
2013
Sayaka Akieda-Asai | Masako Sugiyama | Takashi Miyazawa | Shuichi Koda | Ichiro Okano | Kazuyo Senba | Paul-Emile Poleni | Yoshiyuki Hizukuri | Atsushi Okamoto | Kenichi Yamahara | Eri Mutoh | Fumiyo Aoyama | Akira Sawaguchi | Mayumi Furuya | Mikiya Miyazato | Kenji Kangawa | Yukari Date
A high-fat diet (HFD) is a well-known contributing factor in the development of obesity. Most rats fed HFDs become obese. Those that avoid obesity when fed HFDs are considered diet resistant (DR). We performed a microarray screen to identify genes specific to the mesenteric fat of DR rats and revealed high expression of guanylin and guanylyl cyclase C (GC-C) in some subjects. Our histologic studies revealed that the cellular source of guanylin and GC-C is macrophages. Therefore, we developed double-transgenic (Tg) rats overexpressing guanylin and GC-C in macrophages and found that they were resistant to the effects of HFDs. In the mesenteric fat of HFD-fed Tg rats, Fas and perilipin mRNAs were downregulated, and those of genes involved in fatty acid oxidation were upregulated, compared with the levels in HFD-fed wild-type rats. In vitro studies demonstrated that lipid accumulation was markedly inhibited in adipocytes cocultured with macrophages expressing guanylin and GC-C and that this inhibition was reduced after treatment with guanylin- and GC-C-specific siRNAs. Our results suggest that the macrophagic guanylin-GC-C system contributes to the altered expression of genes involved in lipid metabolism, leading to resistance to obesity.
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