JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice.

Abstract

Type 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice. JTT-553 was repeatedly administered to DIO and KK-A(y) mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-A(y) mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-A(y) mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.

• Authors: Daisuke Tomimoto, Chihiro Okuma, Yukihito Ishii, Akio Kobayashi, Takeshi Ohta, Makoto Kakutani, Tsuneo Imanaka, Nobuya Ogawa
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 129 Issue 1 Pg. 51-8 (Sep 2015) ISSN: 1347-8648 [Electronic] Japan
• PMID: 26354408 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• (5'-(4-amino-7,7-dimethyl-2-trifluoromethyl-7H-pyrimido(4,5-b)(1,4)oxazin-6-yl)-2',3'-dihydrospiro(cyclohexane-1,1'-inden)-4-yl)acetic acid
• Acyl Coenzyme A
• Glucose Transporter Type 4
• Oxazines
• Slc2a4 protein, mouse
• Spiro Compounds
• Tumor Necrosis Factor-alpha
• Dgat1 protein, mouse
• Diacylglycerol O-Acyltransferase
• Glucose

Topics

• Acyl Coenzyme A
• Adipose Tissue (drug effects, metabolism)
• Animals
• Body Weight (drug effects)
• Diabetes Mellitus, Type 2 (genetics, metabolism)
• Diacylglycerol O-Acyltransferase (antagonists & inhibitors)
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Glucose (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Insulin Resistance
• Lipid Metabolism (drug effects)
• Male
• Mice, Inbred C57BL
• Mice, Inbred Strains
• Obesity (etiology, metabolism)
• Oxazines (administration & dosage, pharmacology)
• Spiro Compounds (administration & dosage, pharmacology)
• Tumor Necrosis Factor-alpha (metabolism)
• Weight Gain (drug effects)