Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.
Inhibition of carnitine palmitoyltransferase-1 activity alleviates insulin resistance in diet-induced obese mice.
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DOI：
10.2337/db12-0259
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发表时间：
2013-03
期刊：
影响因子：
7.7
通讯作者：
Lopaschuk GD
中科院分区：
文献类型：
--
作者：
Keung W;Ussher JR;Jaswal JS;Raubenheimer M;Lam VH;Wagg CS;Lopaschuk GD
骨骼肌脂肪酸氧化受损已被认为有助于胰岛素抵抗和葡萄糖耐受不良。然而，增加肌肉脂肪酸氧化可能会导致葡萄糖氧化的相互减少，这可能会损害胰岛素敏感性和葡萄糖耐量。因此，我们研究了抑制线粒体脂肪酸摄取对肥胖胰岛素抵抗小鼠全身葡萄糖耐量和胰岛素敏感性的影响。C57 BL/6小鼠被喂食高脂肪饮食（60%的卡路里来自脂肪）12周以产生胰岛素抵抗。随后用肉毒碱棕榈酰转移酶-1抑制剂奥非尼辛（每日腹腔注射150 mg/kg）治疗小鼠4周，导致全身葡萄糖耐量和胰岛素敏感性改善。奥非尼辛处理的小鼠运动能力增加，伴随着呼吸交换率增加。在腓肠肌中，奥芬新增加丙酮酸脱氢酶活性、膜GLUT 4含量和胰岛素刺激的Akt磷酸化。肌细胞内的脂质中间体水平，包括神经酰胺，长链酰基辅酶A，和甘油二酯，也减少了。我们的研究结果表明，抑制线粒体脂肪酸摄取改善胰岛素敏感性饮食诱导的肥胖小鼠。这与骨骼肌中碳水化合物利用率增加和胰岛素信号传导改善有关，提示肌肉中存在Randle循环。
Impaired skeletal muscle fatty acid oxidation has been suggested to contribute to insulin resistance and glucose intolerance. However, increasing muscle fatty acid oxidation may cause a reciprocal decrease in glucose oxidation, which might impair insulin sensitivity and glucose tolerance. We therefore investigated what effect inhibition of mitochondrial fatty acid uptake has on whole-body glucose tolerance and insulin sensitivity in obese insulin-resistant mice. C57BL/6 mice were fed a high-fat diet (60% calories from fat) for 12 weeks to develop insulin resistance. Subsequent treatment of mice for 4 weeks with the carnitine palmitoyltransferase-1 inhibitor, oxfenicine (150 mg/kg i.p. daily), resulted in improved whole-body glucose tolerance and insulin sensitivity. Exercise capacity was increased in oxfenicine-treated mice, which was accompanied by an increased respiratory exchange ratio. In the gastrocnemius muscle, oxfenicine increased pyruvate dehydrogenase activity, membrane GLUT4 content, and insulin-stimulated Akt phosphorylation. Intramyocellular levels of lipid intermediates, including ceramide, long-chain acyl CoA, and diacylglycerol, were also decreased. Our results demonstrate that inhibition of mitochondrial fatty acid uptake improves insulin sensitivity in diet-induced obese mice. This is associated with increased carbohydrate utilization and improved insulin signaling in the skeletal muscle, suggestive of an operating Randle Cycle in muscle.
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影响因子：
120.7
作者：
Flegal, KM;Carroll, MD;Johnson, CL
通讯作者：
Johnson, CL
影响因子：
7.7
作者：
Iglesias, MA;Ye, JM;Kraegen, EW
通讯作者：
Kraegen, EW
影响因子：
3.1
作者：
BACHMANN, E;WEBER, E
通讯作者：
WEBER, E
DOI：
10.1152/ajpregu.1998.274.2.r524
发表时间：
1998-02-01
影响因子：
2.8
作者：
Deems, RO;Anderson, RC;Foley, JE
通讯作者：
Foley, JE
影响因子：
7.7
作者：
Dobbins, RL;Szczepaniak, LS;McGarry, JD
通讯作者：
McGarry, JD