title: JTP-103237, a novel monoacylglycerol acyltransferase inhibitor, modulates fat absorption and prevents diet-induced obesity.
abstract: Monoacylglycerol acyltransferase 2 (MGAT2) plays an important role in intestinal fat absorption. We discovered the novel MGAT2 inhibitor, JTP-103237, and evaluated its pharmacological profile. JTP-103237 selectively inhibited MGAT2 without remarkable species differences and reduced absorbed lipids in circulation. After lipid administration, JTP-103237 slightly but significantly decreased triglyceride content in proximal small intestine and significantly increased the lipids content in the distal small intestine. In addition, JTP-103237 significantly increased MGAT substrate (monoacylglycerol and fatty acid) content in the small intestine. JTP-103237 increased plasma peptide YY levels after lipid loading and reduced food intake in a dietary fat-dependent manner. After chronic treatment, JTP-103237 significantly decreased body weight and increased O2 consumption in the early dark phase in high fat diet induced obese (DIO) mice. Moreover, JTP-103237 improved glucose tolerance and decreased fat weight and hepatic triglyceride content in DIO mice. Our findings indicate that JTP-103237 prevents diet-induced obesity by inhibiting intestinal MGAT2 and has unique properties as a drug for the treatment of obesity.
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Chihiro
authors: C
authors: Okuma
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. Electronic address: takeshi.ota@jt.com.
authors: Takeshi
authors: T
authors: Ohta
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Hironobu
authors: H
authors: Tadaki
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Hiromi
authors: H
authors: Hamada
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Tomohiro
authors: T
authors: Oda
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Hideyuki
authors: H
authors: Taniuchi
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Kenji
authors: K
authors: Yamanaka
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Yukihito
authors: Y
authors: Ishii
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Yasuhiro
authors: Y
authors: Ohe
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Shinji
authors: S
authors: Yata
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Jun
authors: J
authors: Nishiu
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Yusuke
authors: Y
authors: Aratsu
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Shinichi
authors: S
authors: Oshida
authors: Laboratory of Animal Physiology and Functional Anatomy, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors: Shinichi
authors: S
authors: Kume
authors: Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan.
authors: Makoto
authors: M
authors: Kakutani
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D019556:COS Cells; D002522:Chlorocebus aethiops; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D019894:Peptide YY / Q000097:blood; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C000606936:7-(4,6-di-tert-butylpyrimidin-2-yl)-3-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro(1,2,4)triazolo(4,3-a)pyrazine; D010879:Piperazines; D014230:Triazoles; D019894:Peptide YY; D000217:Acyltransferases; C021802:2-acylglycerol O-acyltransferase
keywords: JTP-103237; Monoacylglycerol acyltransferase; Obesity; Satiety