Metabolic remodeling of white adipose tissue in obesity
Metabolic remodeling of white adipose tissue in obesity
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DOI：
10.1152/ajpendo.00271.2013
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发表时间：
2014-08-01
影响因子：
5.1
通讯作者：
Hill, Bradford G.
中科院分区：
文献类型：
--
作者：
Cummins, Timothy D.;Holden, Candice R.;Hill, Bradford G.
脂肪组织代谢是肥胖和全身能量消耗的关键调节器；然而，白色脂肪组织（WAT）发生的代谢变化与肥胖仍不清楚。本研究的目的是了解WAT与肥胖发生的代谢和生物能量变化。野生型（C57BL/6J）小鼠与低脂喂养小鼠相比，高脂喂养小鼠全身脂肪显著增加，(V) over dot（O2）、(V) over dot（CO2）和呼吸交换比显著降低，葡萄糖和胰岛素耐量恶化。代谢组学分析显示，WAT在脂质、氨基酸、碳水化合物、核苷酸和能量代谢方面发生了显著变化。高脂喂养小鼠的组织中琥珀酸盐和苹果酸盐水平升高，通过骨质增生进入克雷布斯循环的代谢物大多减少，表明线粒体代谢发生了改变。尽管基础耗氧量和线粒体DNA丰度没有变化，但高脂饮食小鼠的WAT中柠檬酸合成酶活性降低了50%以上，对FCCP的反应增加。此外，在HFD治疗6周后，Pgc1a下调，Cox7a1上调。高脂饮食12周后，线粒体呼吸链或基质中几种蛋白质的丰度降低。这些变化伴随着Parkin和Pink1的升高，p62和LC3-I的降低，以及提示自噬和线粒体重塑的超微结构变化。这些研究表明，代谢和自噬的协调重组可能有助于肥胖脂肪组织的肥大和变白。
Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower (V) over dot(O2), (V) over dot(CO2), and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity.