Katterle Yvonne, Keipert Susanne, Hof Jana, Klaus Susanne
German Institute of Human Nutrition in Potsdam-Rehbruecke, Group of Energy Metabolism, Nuthetal, Germany.
Physiol Genomics. 2008 Feb 19;32(3):352-9. doi: 10.1152/physiolgenomics.00194.2007. Epub 2007 Nov 27.
We evaluated the effect of skeletal muscle mitochondrial uncoupling on energy and glucose metabolism under different diets. For 3 mo, transgenic HSA-mUCP1 mice with ectopic expression of uncoupling protein 1 in skeletal muscle and wild-type littermates were fed semisynthetic diets with varying macronutrient ratios (energy % carbohydrate-protein-fat): HCLF (41:42:17), HCHF (41:16:43); LCHF (11:45:44). Body composition, energy metabolism, and insulin resistance were assessed by NMR, indirect calorimetry, and insulin tolerance test, respectively. Gene expression in different organs was determined by real-time PCR. In wild type, both high-fat diets led to an increase in body weight and fat. HSA-mUCP1 mice considerably increased body fat on HCHF but stayed lean on the other diets. Irrespective of differences in body fat content, HSA-mUCP1 mice showed higher insulin sensitivity and decreased plasma insulin and liver triglycerides. Respiratory quotient and gene expression indicated overall increased carbohydrate oxidation of HSA-mUCP1 but a preferential channeling of fatty acids into muscle rather than liver with high-fat diets. Evidence for increased lipogenesis in white fat of HSA-mUCP1 mice suggests increased energy dissipating substrate cycling. Retinol binding protein 4 expression in white fat was increased in HSA-mUCP1 mice despite increased insulin sensitivity, excluding a causal role in the development of insulin resistance. We conclude that skeletal muscle mitochondrial uncoupling does not protect from the development of obesity in all circumstances. Rather it can lead to a "healthy" obese phenotype by preserving insulin sensitivity and a high metabolic flexibility, thus protecting from the development of obesity associated disturbances of glucose homeostasis.
我们评估了骨骼肌线粒体解偶联在不同饮食条件下对能量和葡萄糖代谢的影响。连续3个月，给骨骼肌中异位表达解偶联蛋白1的转基因HSA - mUCP1小鼠及其野生型同窝小鼠喂食具有不同常量营养素比例（能量%碳水化合物 - 蛋白质 - 脂肪）的半合成饮食：HCLF（41:42:17）、HCHF（41:16:43）、LCHF（11:45:44）。分别通过核磁共振、间接量热法和胰岛素耐量试验评估身体组成、能量代谢和胰岛素抵抗。通过实时PCR测定不同器官中的基因表达。在野生型中，两种高脂肪饮食均导致体重和脂肪增加。HSA - mUCP1小鼠在HCHF饮食上体脂显著增加，但在其他饮食上保持消瘦。无论体脂含量存在差异，HSA - mUCP1小鼠均表现出更高的胰岛素敏感性，且血浆胰岛素和肝脏甘油三酯降低。呼吸商和基因表达表明，HSA - mUCP1小鼠总体碳水化合物氧化增加，但在高脂肪饮食下脂肪酸优先进入肌肉而非肝脏。HSA - mUCP1小鼠白色脂肪中脂肪生成增加的证据表明能量耗散底物循环增加。尽管胰岛素敏感性增加，但HSA - mUCP1小鼠白色脂肪中视黄醇结合蛋白4表达增加，排除了其在胰岛素抵抗发生中的因果作用。我们得出结论，骨骼肌线粒体解偶联并非在所有情况下都能预防肥胖的发生。相反，它可以通过保持胰岛素敏感性和高代谢灵活性导致一种“健康的”肥胖表型，从而预防与肥胖相关的葡萄糖稳态紊乱的发生。
