Hoeks J, Hesselink M K C, Russell A P, Mensink M, Saris W H M, Mensink R P, Schrauwen P
Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
Diabetologia. 2006 Oct;49(10):2419-26. doi: 10.1007/s00125-006-0369-2. Epub 2006 Aug 1.
AIMS/HYPOTHESIS: Peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PPARGC1), a coactivator regulating the transcription of genes involved in oxidative metabolism, is downregulated in patients with type 2 diabetes and in their first-degree relatives. Whether this downregulation is a cause or effect of early aberrations in the development of insulin resistance, such as disturbances in fat metabolism, is unknown. We examined whether lipid-induced insulin resistance was associated with downregulation of expression of skeletal muscle genes involved in oxidative metabolism and mitochondrial biogenesis in humans.
Nine healthy lean male subjects underwent a 6-h hyperinsulinaemic-euglycaemic clamp with simultaneous infusion of either a lipid emulsion or glycerol as a control. Blood was sampled at regular time points and muscle biopsies were taken before and after every test. Intramuscular triacylglycerol (IMTG) content was determined by Oil Red O staining and gene expression was measured by quantitative PCR.
Lipid infusion resulted in a approximately 2.7-fold increase in plasma NEFA levels and a 31+/-6% decrease in insulin sensitivity (p=0.001). The infusion of lipids resulted in a approximately 1.6-fold increase in IMTG (p=0.02), whereas during the clamp with glycerol infusion IMTG tended to decrease to approximately 53% of preinfusion levels (p=0.065). Lipid infusion decreased PPARGC1A, PPARGC1B and PPARA expression to approximately 61, 77 and approximately 52% of basal values respectively, whereas expression of uncoupling protein 3 was upregulated 1.8-fold (all p<0.05).
CONCLUSIONS/INTERPRETATION: Acute elevation of plasma NEFA levels, leading to muscular fat accumulation and insulin resistance, downregulates PPARGC1A, PPARGC1B and PPARA expression, suggesting that the decrease in PPARGC1 expression observed in the (pre)diabetic state may be the result, rather than the cause of lipid-induced insulin resistance.
目的/假设：过氧化物酶体增殖物激活受体（PPAR）-γ共激活因子-1（PPARGC1）是一种调节参与氧化代谢的基因转录的共激活因子，在2型糖尿病患者及其一级亲属中表达下调。这种下调是胰岛素抵抗早期异常（如脂肪代谢紊乱）的原因还是结果尚不清楚。我们研究了脂质诱导的胰岛素抵抗是否与人类参与氧化代谢和线粒体生物发生的骨骼肌基因表达下调有关。
9名健康瘦男性受试者接受了6小时的高胰岛素-正常血糖钳夹试验，同时输注脂质乳剂或甘油作为对照。在规定时间点采血，并在每次试验前后进行肌肉活检。通过油红O染色测定肌肉内三酰甘油（IMTG）含量，通过定量PCR测量基因表达。
输注脂质导致血浆非酯化脂肪酸（NEFA）水平升高约2.7倍，胰岛素敏感性降低31±6%（p=0.001）。脂质输注导致IMTG增加约1.6倍（p=0.02），而在输注甘油的钳夹试验期间，IMTG倾向于降至输注前水平的约53%（p=0.065）。脂质输注使PPARGC1A、PPARGC1B和PPARA的表达分别降至基础值的约61%、77%和约52%，而解偶联蛋白3的表达上调1.8倍（所有p<0.05）。
结论/解读：血浆NEFA水平的急性升高导致肌肉脂肪堆积和胰岛素抵抗，下调了PPARGC1A、PPARGC1B和PPARA的表达，这表明在糖尿病前期状态下观察到的PPARGC1表达降低可能是脂质诱导的胰岛素抵抗的结果而非原因。
