title: Cetilistat (ATL-962), a novel pancreatic lipase inhibitor, ameliorates body weight gain and improves lipid profiles in rats.
abstract: Cetilistat is a novel inhibitor of pancreatic lipase. The aim of this report is to evaluate the anti-obesity action of cetilistat in diet-induced obesity (DIO) rats. Cetilistat inhibited rat and human pancreatic lipase activity with an IC (50) of 54.8 nmol/l, and 5.95 nmol/l, respectively, meaning that it is 9.2 times more potent for human pancreatic lipase than for that of rat. Cetilistat was orally administered simultaneously with fat emulsion to Sprague-Dawley rats. Plasma triglyceride (TG) concentrations were measured before and after oral fat loading. The elevation in plasma triglyceride concentration by oral fat loading was reduced by cetilistat in a dose-dependent manner at 3, 10, 30, and 100 mg/kg, indicating that cetilistat reduces intestinal fat absorption in rats. Cetilistat was administered to DIO F344 rats as food admixture in a high-fat diet at 4.9, 14.9, or 50.7 mg/kg/day for three weeks. Both triglyceride and nonesterified fatty acid content in the feces were dose-dependently and drastically increased, suggesting the intestinal breakdown of fat and excretion. Body weight (BW) gain and white adipose tissue (WAT) weight were reduced in a dose-dependent manner. In addition, leptin, TG, and total cholesterol (TC) in plasma were reduced and there were no reports of oily stools. These results suggest that cetilistat ameliorates obesity and hyperlipidemia in DIO rats, a plausible animal model of the most common type of human obesity.
authors.affiliation: Pharmacology Research Laboratories 1, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan. Yamada_Yukio@takeda.co.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Yamada
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: H
authors.initials: H
authors.lastname: Ogino
authors.forename: S
authors.initials: S
authors.lastname: Ashina
authors.forename: K
authors.initials: K
authors.lastname: Kato
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents; D048588:Benzoxazines / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D004032:Diet; D004041:Dietary Fats / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005243:Feces / Q000737:chemistry; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D020799:Pancrelipase / Q000037:antagonists & inhibitors*; D051381:Rats; D011916:Rats, Inbred F344; D014280:Triglycerides / Q000097:blood; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D019440:Anti-Obesity Agents; D048588:Benzoxazines; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D014280:Triglycerides; D020799:Pancrelipase; D002784:Cholesterol; C520092:cetilistat