Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.
Resistance to high-fat diet-induced obesity and insulin resistance in mice with very long-chain acyl-CoA dehydrogenase deficiency.
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DOI：
10.1016/j.cmet.2010.03.012
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发表时间：
2010-05-05
期刊：
影响因子：
29
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Zhang D;Christianson J;Liu ZX;Tian L;Choi CS;Neschen S;Dong J;Wood PA;Shulman GI
线粒体脂肪酸氧化为细胞代谢提供了重要的能量来源，线粒体脂肪酸氧化减少与2型糖尿病的发病机制有关。与WT小鼠相比，具有线粒体脂肪酸氧化酶、极长链酰基辅酶A脱氢酶（VLCAD）遗传缺陷的小鼠表现出肝脏、肌肉和棕色脂肪组织中脂肪酸氧化增加以及全身呼吸商降低。此外，VLCAD−/−小鼠免受脂肪诱导的肝脏和肌肉胰岛素抵抗，这与细胞内二酰基甘油含量减少以及肝脏和肌肉中蛋白激酶Cε和蛋白激酶Cθ活性降低有关。VLCAD−/−小鼠的胰岛素敏感性增加与肝脏和肌肉AMPK活性增加以及肌肉和棕色脂肪组织中PPARα表达增加有关。总之，这些数据表明，VLCAD−/−小鼠由于AMPK（肝脏和肌肉）和PPARα（肌肉和BAT）活性的慢性激活导致脂肪酸氧化增加和肌细胞内和肝细胞二酰甘油含量降低而免受饮食诱导的肥胖和胰岛素抵抗。此外，这些数据表明，由于这些补偿机制，线粒体功能障碍可能会矛盾地导致胰岛素敏感性增加。
Mitochondrial fatty acid oxidation provides an important energy source for cellular metabolism and decreased mitochondrial fatty acid oxidation has been implicated in the pathogenesis of type 2 diabetes. Paradoxically, mice with an inherited deficiency of the mitochondrial fatty acid oxidation enzyme, very long chain acyl-CoA dehydrogenase (VLCAD), manifested increased fatty acid oxidation in liver, muscle and brown adipose tissue and a lower whole body respiratory quotient compared to WT mice. Moreover, VLCAD−/− mice were protected from fat-induced liver and muscle insulin resistance, which was associated with reduced intracellular diacylglycerol content and decreased activity of protein kinase Cε and protein kinase Cθ in liver and muscle respectively. The increased insulin sensitivity in the VLCAD−/− mice was associated with increased liver and muscle AMPK activity and increased PPARα expression in muscle and brown adipose tissue. Taken together these data suggest that VLCAD−/− mice were protected from diet-induced obesity and insulin resistance due to chronic activation of AMPK (liver and muscle) and PPARα (muscle and BAT) activity resulting in increased fatty acid oxidation and decreased intramyocellular and hepatocellular diacylglycerol content. Furthermore these data demonstrate that mitochondrial dysfunction can paradoxically result in increased insulin sensitivity due to these compensatory mechanisms.
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影响因子：
82.9
作者：
Obici, S;Feng, ZH;Rossetti, L
通讯作者：
Rossetti, L
影响因子：
4.8
作者：
Fan, CY;Pan, J;Reddy, JK
通讯作者：
Reddy, JK
DOI：
10.1073/pnas.1032913100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Patti, ME;Butte, AJ;Mandarino, LJ
通讯作者：
Mandarino, LJ
影响因子：
64.5
作者：
Pospisilik, J. Andrew;Knauf, Claude;Penninger, Josef M.
通讯作者：
Penninger, Josef M.
影响因子：
6.1
作者：
Doh, KO;Kim, YW;Kim, JY
通讯作者：
Kim, JY