Abstract
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.
Footnotes
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.176560.
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ABBREVIATIONS:
- PYY
- peptide YY
- GLP-1
- glucagon-like peptide-1
- CCK
- cholecystokinin
- MTP
- microsomal triglyceride transfer protein
- JTT-130
- diethyl-2-({3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl) amino] phenyl}acetyloxymethyl)-2-phenylmalonate
- ELISA
- enzyme-linked immunosorbent assay.
- Received October 26, 2010.
- Accepted December 6, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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