Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes / metabolism
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Animals
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Cholesterol / blood
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Diet, High-Fat / adverse effects*
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Fatty Acids, Nonesterified / blood
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Gastrointestinal Hormones / deficiency
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Gastrointestinal Hormones / genetics
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Gastrointestinal Hormones / metabolism*
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Gene Expression Regulation
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Gene Knock-In Techniques
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Insulin / blood
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Liver / metabolism
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Macrophages / enzymology
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Macrophages / metabolism*
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Macrophages, Peritoneal / enzymology
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Macrophages, Peritoneal / metabolism
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Male
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Mesentery / cytology*
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Natriuretic Peptides / deficiency
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Natriuretic Peptides / genetics
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Natriuretic Peptides / metabolism*
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Oxidation-Reduction
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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Rats
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Rats, Transgenic
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Receptors, Enterotoxin
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Receptors, Guanylate Cyclase-Coupled / deficiency
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Receptors, Guanylate Cyclase-Coupled / genetics
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Receptors, Guanylate Cyclase-Coupled / metabolism*
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Receptors, Peptide / deficiency
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Receptors, Peptide / genetics
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Receptors, Peptide / metabolism*
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Triglycerides / blood
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Triglycerides / metabolism
Substances
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Fatty Acids, Nonesterified
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Gastrointestinal Hormones
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Insulin
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Natriuretic Peptides
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Peptide
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Triglycerides
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guanylin
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Cholesterol
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Receptors, Enterotoxin
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Receptors, Guanylate Cyclase-Coupled