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

  • J Pharmacol Sci. 2015 Sep;129(1):51-8. doi: 10.1016/j.jphs.2015.08.005.
Daisuke Tomimoto  1 ,  Chihiro Okuma  2 ,  Yukihito Ishii  2 ,  Akio Kobayashi  3 ,  Takeshi Ohta  2 ,  Makoto Kakutani  2 ,  Tsuneo Imanaka  4 ,  Nobuya Ogawa  2
Affiliations
  • 1. Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. Electronic address: [email protected].
  • 2. Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
  • 3. Toxicology Research Lab., Central Pharmaceutical Research Institute, Japan Tobacco Inc., 23 Naganuki, Hadano, Kanagawa, 257-0024, Japan.
  • 4. Cell Biology Laboratory, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630, Sugitani, Toyama-shi, Toyama, 930-0194, Japan.
PMID: 26354408 DOI: 10.1016/j.jphs.2015.08.005
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.

Keywords
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1; Insulin resistance; Obesity; Triacylglycerol; Type 2 diabetes.
Products