Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity
Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity
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DOI：
10.1073/pnas.0706794104
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发表时间：
2007-10-16
影响因子：
11.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Choi, Cheol Soo;Savage, David B.;Shulman, Gerald I.
乙酰辅酶a羧化酶2 (ACC)2是线粒体脂肪氧化的关键调节因子。为了研究ACC2缺失对全身能量代谢的影响，我们测量了喂食常规或高脂肪饮食的ACC2（-1-）和WT对照小鼠的底物氧化和总能量消耗的变化。为了确定体内胰岛素的作用，我们还测量了喂食高脂肪饮食的Acc2（-1-）和WT对照小鼠在高胰岛素-正糖钳夹期间全身胰岛素刺激的肝脏和肌肉葡萄糖代谢。与先前的研究表明脂肪氧化增加可能导致葡萄糖氧化降低相反，Acc2（-1）小鼠的脂肪和碳水化合物氧化同时增加。脂肪和碳水化合物氧化的增加导致总能量消耗的增加，脂肪和瘦体重的减少以及饮食引起的肥胖的预防。此外，Acc2（1-）小鼠可免受脂肪诱导的外周和肝脏胰岛素抵抗。胰岛素刺激下葡萄糖代谢的改善与肌肉和肝脏中二酰基甘油含量的降低、肌肉中PKC0活性和肝脏中PKC epsilon活性的降低以及胰岛素刺激下这些组织中Akt2活性的增加有关。结合先前的研究表明，Acc2（-1）小鼠具有正常的寿命，这些数据表明，Acc2抑制是治疗肥胖和2型糖尿病的可行治疗选择。
Acetyl-CoA carboxylase 2 (ACC)2 is a key regulator of mitochondrial fat oxidation. To examine the impact of ACC2 deletion on whole-body energy metabolism, we measured changes in substrate oxidation and total energy expenditure in Acc2(-1-) and WT control mice fed either regular or high-fat diets. To determine insulin action in vivo, we also measured whole-body insulinstimulated liver and muscle glucose metabolism during a hyperinsulinernic-euglycemic clamp in Acc2(-1-) and WT control mice fed a high-fat diet. Contrary to previous studies that have suggested that increased fat oxidation might result in lower glucose oxidation, both fat and carbohydrate oxidation were simultaneously increased in Acc2(-1-) mice. This increase in both fat and carbohydrate oxidation resulted in an increase in total energy expenditure, reductions in fat and lean body mass and prevention from diet-induced obesity. Furthermore, Acc2(-1-) mice were protected from fat-induced peripheral and hepatic insulin resistance. These improvements in insulin-stimulated glucose metabolism were associated with reduced diacylglycerol content in muscle and liver, decreased PKC0 activity in muscle and PKC epsilon activity in liver, and increased insulin-stimulated Akt2 activity in these tissues. Taken together with previous work demonstrating that Acc2(-1-) mice have a normal lifespan, these data suggest that Acc2 inhibition is a viable therapeutic option for the treatment of obesity and type 2 diabetes.