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

PLoS One. 2016 Mar 3;11(3):e0150976. doi: 10.1371/journal.pone.0150976. eCollection 2016.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis
  • Anti-Obesity Agents / pharmacology*
  • Diabetes Mellitus, Experimental / chemically induced
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / pathology
  • Diet, High-Fat
  • Dietary Fats / metabolism
  • Diglycerides / antagonists & inhibitors
  • Diglycerides / biosynthesis
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacology*
  • Fasting
  • Gene Expression
  • High-Throughput Screening Assays
  • Hyperlipidemias / drug therapy*
  • Hyperlipidemias / enzymology
  • Hyperlipidemias / pathology
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Insulin Resistance
  • Intestine, Small / drug effects
  • Intestine, Small / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Acetylglucosaminyltransferases / antagonists & inhibitors*
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Obesity / pathology
  • Streptozocin
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*
  • Triglycerides / antagonists & inhibitors
  • Triglycerides / biosynthesis
  • Weight Gain / drug effects


  • Anti-Obesity Agents
  • Dietary Fats
  • Diglycerides
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Indoles
  • N-(4-chloro-2,6-difluorophenyl)-1-(5-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimidin-2-yl)-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide
  • Sulfonamides
  • Triglycerides
  • Streptozocin
  • N-Acetylglucosaminyltransferases
  • alpha-1,6-mannosyl-glycoprotein beta-1,2-N-acetylglucosaminyltransferase

Grant support

This study was financially supported by Takeda Pharmaceutical Company Limited. Employees of Takeda played roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.