Mitochondrial uncoupling as a target for drug development for the treatment of obesity.
Mitochondrial uncoupling as a target for drug development for the treatment of obesity.
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DOI：
10.1046/j.1467-789x.2001.00043.x
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发表时间：
2001-11-01
期刊：
影响因子：
--
通讯作者：
Brand, M D
中科院分区：
文献类型：
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作者：
Harper, J A;Dickinson, K;Brand, M D
线粒体质子循环是基础或标准代谢率的重要组成部分，因此线粒体的进一步解偶联可能是增加能量消耗的好方法，并且代表了治疗肥胖症的良好药理学靶标。通过2，4-二硝基苯酚的解偶联在过去已经以这种方式使用并取得了显著的成功，并且甲状腺激素治疗诱导体重减轻的一些效果也可能是由于解偶联。饮食可以改变线粒体膜中磷脂脂肪酰基的模式，这可能是体内解偶联的途径。能量消耗可以通过直接或通过β 3-肾上腺素受体激动剂刺激棕色脂肪细胞中解偶联蛋白1（UCP 1）的活性来增加。许多组织中的UCP 2、骨骼肌中的UCP 3和腺嘌呤核苷酸移位酶也被提议为可能的药物靶点。肌肉或棕色脂肪细胞线粒体的特异性解偶联仍然是开发抗肥胖药物的有吸引力的靶点。
Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, so further uncoupling of mitochondria may be a good way to increase energy expenditure and represents a good pharmacological target for the treatment of obesity. Uncoupling by 2,4-dinitrophenol has been used in this way in the past with notable success, and some of the effects of thyroid hormone treatment to induce weight loss may also be due to uncoupling. Diet can alter the pattern of phospholipid fatty acyl groups in the mitochondrial membrane, and this may be a route to uncoupling in vivo. Energy expenditure can be increased by stimulating the activity of uncoupling protein 1 (UCP1) in brown adipocytes either directly or through beta 3-adrenoceptor agonists. UCP2 in a number of tissues, UCP3 in skeletal muscle and the adenine nucleotide translocase have also been proposed as possible drug targets. Specific uncoupling of muscle or brown adipocyte mitochondria remains an attractive target for the development of antiobesity drugs.