Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1
Dissociation of obesity and insulin resistance in transgenic mice with skeletal muscle expression of uncoupling protein 1
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DOI：
10.1152/physiolgenomics.00194.2007
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发表时间：
2008-02-19
影响因子：
4.6
通讯作者：
Klaus, Susanne
中科院分区：
文献类型：
--
作者：
Katterle, Yvonne;Keipert, Susanne;Klaus, Susanne
我们评估了骨骼肌线粒体解偶联对不同饮食条件下能量和葡萄糖代谢的影响。对于3个月，骨骼肌中异位表达解偶联蛋白1的转基因HSA-mUCP 1小鼠和野生型同窝出生的小鼠，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）的半合成饲料：HCLF（41：42：17），HCHF（41：16：43）; LCHF（11：45：44）。分别采用核磁共振、间接量热法和胰岛素耐量试验评估身体成分、能量代谢和胰岛素抵抗。通过实时荧光定量PCR测定不同器官中的基因表达。在野生型中，两种高脂肪饮食都导致体重和脂肪增加。HSA-mUCP 1小鼠在HCHF上显著增加了体脂，但在其他饮食上保持精益。不考虑体脂含量的差异，HSA-mUCP 1小鼠显示出更高的胰岛素敏感性和降低的血浆胰岛素和肝脏甘油三酯。呼吸商和基因表达表明HSA-mUCP 1的碳水化合物氧化总体增加，但在高脂饮食下脂肪酸优先进入肌肉而不是肝脏。HSA-mUCP 1小鼠的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-mUCP 1小鼠中白色脂肪中的视黄醇结合蛋白4表达增加，排除了在胰岛素抵抗发展中的因果作用。我们的结论是，骨骼肌线粒体解偶联并不能在所有情况下防止肥胖的发展。相反，它可以通过保持胰岛素敏感性和高代谢灵活性而导致“健康的”肥胖表型，从而防止与葡萄糖稳态紊乱相关的肥胖症的发展。
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.