Mera Paula, Bentebibel Assia, López-Viñas Eduardo, Cordente Antonio G, Gurunathan Chandrashekaran, Sebastián David, Vázquez Irene, Herrero Laura, Ariza Xavier, Gómez-Puertas Paulino, Asins Guillermina, Serra Dolors, García Jordi, Hegardt Fausto G
Department of Biochemistry and Molecular Biology and IBUB (Institute of Biomedicine University of Barcelona), Spain.
Biochem Pharmacol. 2009 Mar 15;77(6):1084-95. doi: 10.1016/j.bcp.2008.11.020. Epub 2008 Nov 27.
Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes. However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty-acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.
在啮齿动物中，向中枢神经系统给药C75会导致食欲减退和体重减轻，这表明C75是一种治疗肥胖症和2型糖尿病的潜在药物。然而，这种作用的潜在机制尚不清楚。在此我们表明，C75-CoA可在体外和体内由C75化学合成产生，并且它是肉碱棕榈酰转移酶1（CPT1）的有效抑制剂，而CPT1是脂肪酸氧化的限速步骤。三维对接和动力学分析支持C75-CoA对CPT1的抑制作用。向大鼠中枢神经系统给药C75会导致C75-CoA生成、CPT1受抑制以及体重和食物摄入量降低。我们的结果表明，对CPT1的抑制作用，进而导致下丘脑脂肪酸可用性增加，是C75减少食物摄入量的药理机制。
