JTP-103237, a novel monoacylglycerol acyltransferase inhibitor, modulates fat absorption and prevents diet-induced obesity

• Published in: European journal of pharmacology Vol. 758; pp. 72 - 81
• Main Authors: Okuma, Chihiro, Ohta, Takeshi, Tadaki, Hironobu, Hamada, Hiromi, Oda, Tomohiro, Taniuchi, Hideyuki, Yamanaka, Kenji, Ishii, Yukihito, Ohe, Yasuhiro, Yata, Shinji, Nishiu, Jun, Aratsu, Yusuke, Oshida, Shinichi, Kume, Shinichi, Kakutani, Makoto
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.07.2015
• Subjects: Acyltransferases - antagonists & inhibitors; Animals; Body Weight - drug effects; Cercopithecus aethiops; COS Cells; Diet, High-Fat - adverse effects; Eating - drug effects; Glucose Tolerance Test; Humans; Intestinal Absorption - drug effects; JTP-103237; Lipid Metabolism - drug effects; Male; Mice; Monoacylglycerol acyltransferase; Obesity; Obesity - chemically induced; Obesity - metabolism; Obesity - prevention & control; Oxygen Consumption - drug effects; Peptide YY - blood; Piperazines - pharmacology; Rats; Satiety; Triazoles - pharmacology; Satiety; Obesity; JTP-103237; Monoacylglycerol acyltransferase
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.03.072

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.