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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 336; no. 3; pp. 850 - 856
• Main Authors: Hata, Takahiro, Mera, Yasuko, Ishii, Yukihito, Tadaki, Hironobu, Tomimoto, Daisuke, Kuroki, Yukiharu, Kawai, Takashi, Ohta, Takeshi, Kakutani, Makoto
• Format: Journal Article
• Language: English
• Published: United States 01.03.2011
• Subjects: Animals; Appetite Depressants - pharmacology; Benzamides - pharmacology; Biomarkers - blood; Carrier Proteins - antagonists & inhibitors; Carrier Proteins - metabolism; Dietary Fats - administration & dosage; Eating - drug effects; Eating - physiology; Gastric Emptying - drug effects; Gastric Emptying - physiology; Glucagon-Like Peptide 1 - blood; Male; Malonates - pharmacology; Peptide YY - blood; Rats; Rats, Sprague-Dawley
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.176560

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.