JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses food intake and gastric emptying with the elevation of plasma peptide YY and glucagon-like peptide-1 in a dietary fat-dependent manner.
The microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. In this study, we investigated the effects of diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate (JTT-130), a novel intestine-specific MTP inhibitor, on food intake, gastric emptying, and gut peptides using Sprague-Dawley rats fed 3.1% fat, 13% fat, or 35% fat diets. JTT-130 treatment suppressed cumulative food intake and gastric emptying in rats fed a 35% fat diet, but not a 3.1% fat diet. In rats fed a 13% fat diet, JTT-130 treatment decreased cumulative food intake but not gastric emptying. In addition, treatment with orlistat, a lipase inhibitor, completely abolished the reduction of food intake and gastric emptying by JTT-130 in rats fed a 35% fat diet. On the other hand, JTT-130 treatment increased the plasma concentrations of gut peptides, peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) but not cholecystokinin, in the portal vein in rats fed a 35% fat diet. These elevations in PYY and GLP-1 were also abolished by treatment with orlistat. Furthermore, JTT-130 treatment in rats fed a 35% fat diet increased the contents of triglycerides and free fatty acids in the intestinal lumen, which might contribute to the elevation of PYY and GLP-1 levels. The present findings indicate that JTT-130 causes satiety responses, decreased food intake, and gastric emptying in a dietary fat-dependent manner, with enhanced production of gut peptides such as PYY and GLP-1 from the intestine.
Japan Tobacco Inc., Central Pharmaceutical Research Institute, Takatsuki, Osaka 569-1125, Japan. takahiro.hata@jt.com
Takahiro
T
Hata
Yasuko
Y
Mera
Yukihito
Y
Ishii
Hironobu
H
Tadaki
Daisuke
D
Tomimoto
Yukiharu
Y
Kuroki
Takashi
T
Kawai
Takeshi
T
Ohta
Makoto
M
Kakutani
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage*; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D008297:Male; D008314:Malonates / Q000494:pharmacology*; D019894:Peptide YY / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley
D001067:Appetite Depressants; D001549:Benzamides; D015415:Biomarkers; D002352:Carrier Proteins; D004041:Dietary Fats; D008314:Malonates; 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