Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding
Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding
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DOI：
10.1007/s00125-013-2913-1
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发表时间：
2013-07-01
期刊：
影响因子：
8.2
通讯作者：
Bruce, C. R.
中科院分区：
文献类型：
--
作者：
Turner, N.;Kowalski, G. M.;Bruce, C. R.
虽然众所周知，饮食诱导的肥胖导致胰岛素抵抗，但胰岛素抵抗起始的确切机制尚不清楚。为了确定可能导致胰岛素抵抗的因素，我们在喂食高脂饮食（HFD）的小鼠中进行了详细的时间过程研究。C57 Bl/6小鼠从3天到16周喂食食物或HFD，并测定葡萄糖耐量和组织特异性胰岛素作用。通过质谱分析组织脂质谱，并测量脂肪组织、肝脏和骨骼肌中的炎症标志物。葡萄糖耐受不良在HFD后3天内发生，在12周内没有进一步恶化。HFD 1周后，通过高胰岛素-正常血钳夹法检测全身胰岛素抵抗，这是由于肝脏胰岛素抵抗。脂肪组织在1周后出现胰岛素抵抗，而骨骼肌在3周时出现胰岛素抵抗，这与葡萄糖处理缺陷一致。有趣的是，在该初始缺陷之后，在任何组织中均未观察到胰岛素敏感性的进一步恶化。当胰岛素抵抗首次出现时，肝脏和肌肉中甘油二酯含量增加，而脂肪组织中胰岛素抵抗的发生与神经酰胺和鞘磷脂的增加有关。脂肪组织炎症仅在HFD 16周时检测到，且与胰岛素抵抗的诱导无关。HFD诱导的全身胰岛素抵抗是由肝脏胰岛素作用受损引发的，并因骨骼肌胰岛素抵抗而加剧，并且与特定生物活性脂质的积累有关。物种。
While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD).C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle.Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance.HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.