Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice
Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice
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DOI：
10.1111/j.1474-9726.2007.00346.x
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发表时间：
2007-12-01
期刊：
影响因子：
7.8
通讯作者：
Kahn, C. Ronald
中科院分区：
文献类型：
--
作者：
Katic, Masa;Kennedy, Adam R.;Kahn, C. Ronald
从秀丽隐杆线虫到人类的许多生物，热量限制、瘦和胰岛素/胰岛素样生长因子1 （IGF-1）受体信号活性降低与寿命延长有关。脂肪特异性胰岛素受体敲除（FIRKO）小鼠代表了一种有趣的二分法，尽管食物摄入量正常或增加，但它们更瘦，寿命更长。为了确定脂肪组织中缺乏胰岛素信号可能产生这种影响的机制，我们在FIRKO和对照小鼠衰老过程中进行了生理和基因表达研究。在全身水平上，FIRKO小鼠显示出基础代谢率和呼吸交换率的增加。对6 - 36月龄FIRKO小鼠白色脂肪组织（WAT）中基因表达的分析显示，与WAT中相同基因的表达相比，核编码线粒体基因持续高表达，这些基因参与糖酵解、三羧酸循环、β -氧化和氧化磷酸化，而对照组的WAT中相同基因的表达随年龄增长而下降。这些基因表达的变化与细胞色素c和细胞色素c氧化酶亚基IV蛋白水平升高、柠檬酸合酶活性升高、过氧化物酶体增殖体激活受体γ辅助激活因子1 α (PGC-1 α)和PGC-1 β表达升高以及FIRKO小鼠WAT线粒体DNA增加有关。总之，这些数据表明，脂肪组织中线粒体活性和代谢率的维持可能是延长FIRKO小鼠寿命的重要因素。
Caloric restriction, leanness and decreased activity of insulin/insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fat-specific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. To determine the mechanisms by which a lack of insulin signaling in adipose tissue might exert this effect, we performed physiological and gene expression studies in FIRKO and control mice as they aged. At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, beta-oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age. These changes in gene expression were correlated with increased cytochrome c and cytochrome c oxidase subunit IV at the protein level, increased citrate synthase activity, increased expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and PGC-1 beta, and an increase in mitochondrial DNA in WAT of FIRKO mice. Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.