Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet

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.-Akieda-Asai, S., M. Sugiyama, T. Miyazawa, S. Koda, I. Okano, K. Senba, P.-E. Poleni, Y. Hizukuri, A. Okamoto, K. Yamahara, E. Mutoh, F. Aoyama, A. Sawaguchi, M. Furuya, M. Miyazato, K. Kangawa, and Y. Date. Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet. J. Lipid Res. 54: 85-96.