Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization

• Published in: PloS one 2016-03, Vol.11 (3), p.e0150976-e0150976
• Main Authors: Take, Kazumi, Mochida, Taisuke, Maki, Toshiyuki, Satomi, Yoshinori, Hirayama, Megumi, Nakakariya, Masanori, Amano, Nobuyuki, Adachi, Ryutaro, Sato, Kenjiro, Kitazaki, Tomoyuki, Takekawa, Shiro
• Format: Article
• Language: English
• Subjects: Acyltransferase; Animals; Anti-Obesity Agents - chemical synthesis; Anti-Obesity Agents - pharmacology; Bariatric surgery; Bioavailability; Biology and Life Sciences; Body weight; Body weight gain; Carnitine; Chemical synthesis; Compound A; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Experimental - pathology; Diacylglycerol; Diet, High-Fat; Dietary Fats - metabolism; Diglycerides; Diglycerides - antagonists & inhibitors; Diglycerides - biosynthesis; Drug dosages; Dyslipidemia; Endocrinology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Fasting; Fatty acids; Fatty liver; Food intake; Gastric bypass; Gastrointestinal surgery; Gene Expression; Glucose; Glycerol; High fat diet; High-throughput screening; High-Throughput Screening Assays; House mouse; Hyperglycemia; Hyperlipidemia; Hyperlipidemias - drug therapy; Hyperlipidemias - enzymology; Hyperlipidemias - pathology; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Indoles - chemical synthesis; Indoles - pharmacology; Inhibition; Insulin; Insulin Resistance; Intestinal bypass; Intestine, Small - drug effects; Intestine, Small - metabolism; Laboratory animals; Lead compounds; Lipids; Lipoproteins; Liver; Male; Medicine and Health Sciences; Metabolic disorders; Metabolic flux; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Acetylglucosaminyltransferases - antagonists & inhibitors; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Obesity; Obesity - drug therapy; Obesity - enzymology; Obesity - pathology; Pharmaceutical industry; Pharmacology; R&D; Research & development; Rodents; Sensitivity analysis; Small intestine; Streptozocin; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Surgery; Triglycerides; Triglycerides - antagonists & inhibitors; Triglycerides - biosynthesis; Type 2 diabetes; Weight Gain - drug effects
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0150976

Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders.