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

Autor: Daisuke Tomimoto, Chihiro Okuma, Yukihito Ishii, Akio Kobayashi, Takeshi Ohta, Makoto Kakutani, Tsuneo Imanaka, Nobuya Ogawa
Jazyk: angličtina
Rok vydání: 2015
Předmět:
Zdroj: Journal of Pharmacological Sciences, Vol 129, Iss 1, Pp 51-58 (2015)
Druh dokumentu: article
ISSN: 1347-8613
DOI: 10.1016/j.jphs.2015.08.005
Popis: 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-Ay 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-Ay 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-Ay mice. These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight.
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