JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses high fat diet-induced obesity and glucose intolerance in Sprague-Dawley rats.
OBJECTIVE
Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on high fat diet-induced obesity and glucose intolerance.


METHODS
Male Sprague-Dawley rats were fed a 3.1% fat diet or a 35% fat diet with or without JTT-130 as a food admixture (0.029%). Food intake, body weight, abdominal fat, hepatic triglyceride, faecal free fatty acids and plasma levels of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were assessed. Plasma levels of glucose and insulin were measured during intraperitoneal glucose tolerance tests. In addition, indirect calorimetry was performed on rats fed with a 35% fat diet.


RESULTS
JTT-130 treatment decreased body weights, abdominal fat and hepatic triglyceride with suppression of food intake and elevation of faecal free fatty acids and plasma GLP-1 and PYY levels in rats fed with the 35% fat diet, whereas no significant effects on these parameters except for increased faecal free fatty acids were observed in rats fed with the 3.1% fat diet. JTT-130 treatment decreased plasma levels of glucose and insulin during intraperitoneal glucose tolerance tests on rats fed with the 35% fat diet, but not on rats fed with the 3.1% fat diet. JTT-130-treated rats showed increased O(2) consumption and CO(2) production on a 35% fat diet.


CONCLUSIONS
JTT-130 suppresses high fat diet-induced obesity and glucose intolerance with suppression of food intake and fat absorption and could be useful for prevention and treatment of obesity and obesity-related insulin resistance.
Japan Tobacco, Central Pharmaceutical Research Institute, Biological/Pharmacological Research Laboratories, Osaka. katherine.esposito@unina2.it
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Hata
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Mera
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Tadaki
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Kuroki
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Kawai
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Ohta
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Kakutani
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects; D004435:Eating / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000517:prevention & control; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D019894:Peptide YY / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
D001549:Benzamides; D015415:Biomarkers; D001786:Blood Glucose; D002352:Carrier Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007328:Insulin; D008314:Malonates; D014280:Triglycerides; C556241:diethyl 2-((3-dimethylcarbamoyl-4-((4'-trifluoromethylbiphenyl-2-carbonyl)amino)phenyl)acetyloxymethyl)-2-phenylmalonate; C106092:microsomal triglyceride transfer protein; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1