Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats
Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats
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DOI：
10.2337/diabetes.50.1.123
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发表时间：
2001-01-01
期刊：
影响因子：
7.7
通讯作者：
McGarry, JD
中科院分区：
文献类型：
--
作者：
Dobbins, RL;Szczepaniak, LS;McGarry, JD
人类受试者的横断面研究使用H-1磁共振波谱（HMRS）来证明胰岛素抵抗与细胞内脂质（IMCL）浓度的相关性比与任何其他确定的危险因素的相关性更紧密。为了进一步探索这两种元素在大鼠体内的相互作用，我们采用了两种策略来促进骨骼肌中的脂质储存，然后评估胰岛素介导的葡萄糖处置的后续变化。正常大鼠分别给予低脂或高脂饮食（20%猪油）4周。另外两组（低脂+乙toxomir和猪油+乙toxomir）食用含有0.01%肉碱棕榈酰基转移酶-1抑制剂r -乙托莫西的饮食，该抑制剂对肝脏和骨骼肌中的酶活性产生慢性阻断。高脂肪饮食和药物治疗均显著损害胰岛素敏感性，用高胰岛素-血糖钳测量。胰岛素介导的葡萄糖处理（IMGD）从低脂组的12.57 +/- 0.72下降到9.79 +/- 0.59、8.96 +/- 0.38和7.32 +/- 0.28 μ mol。分钟(1)。低脂+乙氧索米组、猪油组和猪油+乙氧索米组分别为100 g（-1）。我们使用HMRS来评估离体比目鱼肌的IMCL含量，该方法可以区分肌细胞内的脂肪和与位于肌肉床的污染脂肪细胞相关的脂肪。IMGD与IMCL之间呈紧密的负相关，相关性（R = 0.96）远强于IMGD与脂肪量或体重之间的相关性。总之，富含饱和脂肪的饮食或长时间抑制脂肪酸氧化都会通过与IMCL积累相关的机制损害大鼠的IMGD。
Cross-sectional studies in human subjects have used H-1 magnetic resonance spectroscopy (HMRS) to demonstrate that insulin resistance correlates more tightly with the intramyocellular lipid (IMCL) concentration than with any other identified risk factor. To further explore the interaction between these two elements in the rat, we used two strategies to promote the storage of lipids in skeletal muscle and then evaluated subsequent changes in insulin-mediated glucose disposal. Normal rats received either a low-fat or a high-fat diet (20% lard oil) for 4 weeks. Two additional groups (low-fat + etoxomir and lard + etoxomir) consumed diets containing 0.01% of the carnitine palmitoyltransferase-1 inhibitor, R-etomoxir, which produced chronic blockade of enzyme activity in liver and skeletal muscle. Both the high-fat diet and drug treatment significantly impaired insulin sensitivity, as measured with the hyperinsulinemic-euglycemic clamp. Insulin-mediated glucose disposal (IMGD) fell from 12.57 +/- 0.72 in the low-fat group to 9.79 +/- 0.59, 8.96 +/- 0.38, and 7.32 +/- 0.28 mu mol . min(-1) . 100 g(-1) in the low-fat + etoxomir, lard, and lard + etoxomir groups, respectively. We used HMRS, which distinguishes between fat within the myocytes and fat associated with contaminating adipocytes located in the muscle bed, to assess the IMCL content of isolated soleus muscle. A tight inverse relationship was found between IMGD and IMCL, the correlation (R = 0.96) being much stronger than that seen between IMGD and either fat mass or weight. In conclusion, either a diet rich in saturated fat or prolonged inhibition of fatty acid oxidation impairs IMGD in rats via a mechanism related to the accumulation of IMCL.