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

• Published in: Journal of lipid research Vol. 54; no. 1; pp. 85 - 96
• Main Authors: Akieda-Asai, Sayaka, Sugiyama, Masako, Miyazawa, Takashi, Koda, Shuichi, Okano, Ichiro, Senba, Kazuyo, Poleni, Paul-Emile, Hizukuri, Yoshiyuki, Okamoto, Atsushi, Yamahara, Kenichi, Mutoh, Eri, Aoyama, Fumiyo, Sawaguchi, Akira, Furuya, Mayumi, Miyazato, Mikiya, Kangawa, Kenji, Date, Yukari
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: adipocytes; Adipocytes - metabolism; Animals; Cholesterol - blood; diet resistance; Diet, High-Fat - adverse effects; dietary lipids; Fatty Acids, Nonesterified - blood; Gastrointestinal Hormones - deficiency; Gastrointestinal Hormones - genetics; Gastrointestinal Hormones - metabolism; Gene Expression Regulation; Gene Knock-In Techniques; Insulin - blood; lipid metabolism; Liver - metabolism; Macrophages - enzymology; Macrophages - metabolism; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - metabolism; Male; Mesentery - cytology; Natriuretic Peptides - deficiency; Natriuretic Peptides - genetics; Natriuretic Peptides - metabolism; obesity; Oxidation-Reduction; Rats; Rats, Transgenic; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled - deficiency; Receptors, Guanylate Cyclase-Coupled - genetics; Receptors, Guanylate Cyclase-Coupled - metabolism; Receptors, Peptide - deficiency; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Triglycerides - blood; Triglycerides - metabolism; dietary lipids; adipocytes; diet resistance; obesity; lipid metabolism
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1194/jlr.M029017

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.