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.
Frontier Science Research Center, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Sayaka
S
Akieda-Asai
Masako
M
Sugiyama
Takashi
T
Miyazawa
Shuichi
S
Koda
Ichiro
I
Okano
Kazuyo
K
Senba
Paul-Emile
PE
Poleni
Yoshiyuki
Y
Hizukuri
Atsushi
A
Okamoto
Kenichi
K
Yamahara
Eri
E
Mutoh
Fumiyo
F
Aoyama
Akira
A
Sawaguchi
Mayumi
M
Furuya
Mikiya
M
Miyazato
Kenji
K
Kangawa
Yukari
Y
Date
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000097:blood; D059305:Diet, High-Fat / Q000009:adverse effects*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005768:Gastrointestinal Hormones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D055879:Gene Knock-In Techniques; D007328:Insulin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008643:Mesentery / Q000166:cytology*; D045265:Natriuretic Peptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D055647:Rats, Transgenic; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D005768:Gastrointestinal Hormones; D007328:Insulin; D045265:Natriuretic Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018000:Receptors, Peptide; D014280:Triglycerides; C072685:guanylin; D002784:Cholesterol; D000074261:Receptors, Enterotoxin; D050705:Receptors, Guanylate Cyclase-Coupled