JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice.
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.
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. Electronic address: daisuke.tomimoto@jt.com.
Daisuke
D
Tomimoto
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Chihiro
C
Okuma
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Yukihito
Y
Ishii
Toxicology Research Lab., Central Pharmaceutical Research Institute, Japan Tobacco Inc., 23 Naganuki, Hadano, Kanagawa, 257-0024, Japan.
Akio
A
Kobayashi
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Takeshi
T
Ohta
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Makoto
M
Kakutani
Cell Biology Laboratory, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630, Sugitani, Toyama-shi, Toyama, 930-0194, Japan.
Tsuneo
T
Imanaka
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
Nobuya
N
Ogawa
D000214:Acyl Coenzyme A; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase / Q000037:antagonists & inhibitors*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009765:Obesity / Q000209:etiology* / Q000378:metabolism*; D010078:Oxazines / Q000008:administration & dosage / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
C000603501:(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; D000214:Acyl Coenzyme A; D051275:Glucose Transporter Type 4; D010078:Oxazines; C495693:Slc2a4 protein, mouse; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D005947:Glucose
Acyl CoA:diacylglycerol acyltransferase (DGAT) 1; Insulin resistance; Obesity; Triacylglycerol; Type 2 diabetes