Department of Exercise and Sport Science, East Carolina University, Greenville, North Carolina, USA.
Diabetes. 2010 Jun;59(6):1407-15. doi: 10.2337/db09-1704. Epub 2010 Mar 3.
To determine whether the obesity-related decrement in fatty acid oxidation (FAO) in primary human skeletal muscle cells (HSkMC) is linked with lower mitochondrial content and whether this deficit could be corrected via overexpression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha).
FAO was studied in HSkMC from lean (BMI 22.4 +/- 0.9 kg/m(2); N = 12) and extremely obese (45.3 +/- 1.4 kg/m(2); N = 9) subjects. Recombinant adenovirus was used to increase HSkMC PGC-1alpha expression (3.5- and 8.0-fold), followed by assessment of mitochondrial content (mtDNA and cytochrome C oxidase IV [COXIV]), complete ((14)CO(2) production from labeled oleate), and incomplete (acid soluble metabolites [ASM]) FAO, and glycerolipid synthesis.
Obesity was associated with a 30% decrease (P < 0.05) in complete FAO, which was accompanied by higher relative rates of incomplete FAO ([(14)C]ASM production/(14)CO(2)), increased partitioning of fatty acid toward storage, and lower (P < 0.05) mtDNA (-27%), COXIV (-35%), and mitochondrial transcription factor (mtTFA) (-43%) protein levels. PGC-1alpha overexpression increased (P < 0.05) FAO, mtDNA, COXIV, mtTFA, and fatty acid incorporation into triacylglycerol in both lean and obese groups. Perturbations in FAO, triacylglycerol synthesis, mtDNA, COXIV, and mtTFA in obese compared with lean HSkMC persisted despite PGC-1alpha overexpression. When adjusted for mtDNA and COXIV content, FAO was equivalent between lean and obese groups.
Reduced mitochondrial content is related to impaired FAO in HSkMC derived from obese individuals. Increasing PGC-1alpha protein levels did not correct the obesity-related absolute reduction in FAO or mtDNA content, implicating mechanisms other than PGC-1alpha abundance.
确定原发性人骨骼肌细胞（HSkMC）中与肥胖相关的脂肪酸氧化（FAO）下降是否与线粒体含量较低有关，以及这种缺陷是否可以通过过表达过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）来纠正。
研究了来自瘦（BMI 22.4 +/- 0.9 kg/m2；N = 12）和极度肥胖（45.3 +/- 1.4 kg/m2；N = 9）个体的 HSkMC 的 FAO。使用重组腺病毒增加 HSkMC PGC-1α的表达（3.5-和 8.0 倍），然后评估线粒体含量（mtDNA 和细胞色素 C 氧化酶 IV [COXIV]）、完全（从标记的油酸中产生的（14）CO2）和不完全（酸溶性代谢物 [ASM]）FAO 以及甘油三酯合成。
肥胖与完全 FAO 下降 30%（P < 0.05）相关，这伴随着不完全 FAO 的相对速率更高（（14）CASM 产生/（14）CO2），脂肪酸向储存的分配增加，以及 mtDNA（-27%）、COXIV（-35%）和线粒体转录因子（mtTFA）（-43%）蛋白水平降低（P < 0.05）。PGC-1α过表达增加了（P < 0.05）FAO、mtDNA、COXIV、mtTFA 和脂肪酸掺入甘油三酯，在瘦组和肥胖组中均如此。尽管过表达了 PGC-1α，但肥胖的 HSkMC 中 FAO、甘油三酯合成、mtDNA、COXIV 和 mtTFA 的紊乱仍持续存在。当调整 mtDNA 和 COXIV 含量后，瘦组和肥胖组之间的 FAO 是等效的。
在肥胖个体来源的 HSkMC 中，线粒体含量的减少与 FAO 受损有关。增加 PGC-1α 蛋白水平并不能纠正肥胖相关的 FAO 或 mtDNA 含量的绝对减少，这暗示了除 PGC-1α 丰度以外的机制。
