Cell Metabolism：胰岛素抵抗引发脂肪酸过度氧化
生物谷报道：一种常见假说认为，胰岛素抵抗（insulin resistance）会降低脂肪氧化的发生，此外有研究表明，胰岛素抵抗还会导致胞质内脂质分子的聚集，并破坏胰岛素信号通路。而在2008年1月9日出版的《细胞—代谢》（Cell Metabolism）上，来自美国杜克大学和加拿大的一组科学家发现，肥胖引起的肌肉胰岛素抵抗会导致过度脂肪酸氧化，而非传统认为的减少。
胰岛素抵抗是多种疾病的危险因素，特别是糖尿病和由此引起的多种心血管疾病。胰岛素抵抗产生的原因是胰岛素执行其效应能力不足，因此导致肌肉、脂肪等组织对葡萄糖利用产生障碍。
研究中，科学家们利用目标代谢组学方法发现，在骨骼肌中由于肥胖引起的胰岛素抵抗会产生过度的β氧化，破坏在饥饿—饱胀变化过程中碳水化合物底物的转变，并且损耗三羧酸循环（tricarboxylic acid cycle）中的有机酸中间产物。
在培养的肌管中，科学家通过限制线粒体中的脂肪酸而阻碍脂肪引起的胰岛素抵抗。研究人员还利用缺少丙二酰-CoA脱羧酶（Malonyl-CoA decarboxylase）的小鼠进行了实验，丙二酰-CoA脱羧酶是一种能促进线粒体中β氧化的物质。实验结果表明，这些小鼠表现出了脂肪分解代谢的降低，并且在肌肉存在高浓度长链脂肪酰CoA（acyl-CoA）的情况下表现出食物引起的葡萄糖不耐受的抵抗。
新的研究结果说明，在骨骼肌胰岛素抵抗和脂肪引起的线粒体压力之间存在密切联系。（科学网 何宏辉/编译）
生物谷推荐英文原文：
Cell Metabolism, Vol 7, 45-56, 09 January 2008
Article
Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance
Timothy R. Koves,1,2 John R. Ussher,4 Robert C. Noland,1 Dorothy Slentz,1 Merrie Mosedale,1 Olga Ilkayeva,1 James Bain,1 Robert Stevens,1 Jason R.B. Dyck,4 Christopher B. Newgard,1,2,3 Gary D. Lopaschuk,4 and Deborah M. Muoio1,2,3,
1 Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, NC 27710, USA
2 Department of Medicine, Duke University, Durham, NC 27710, USA
3 Department of Pharmacology & Cancer Biology, Duke University, Durham, NC 27710, USA
4 Cardiovascular Research Group, University of Alberta, Edmonton, AB T6G 2S2, Canada
Corresponding author
Deborah M. Muoio
muoio@duke.edu
Summary
Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive β-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial β-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd−/− mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.
- 众说风云 (已有0条评论)
