Acute and long-term administration of palmitoylcarnitine induces muscle-specific insulin resistance in mice
Acute and long-term administration of palmitoylcarnitine induces muscle-specific insulin resistance in mice
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DOI：
10.1002/biof.1378
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发表时间：
2017-09-01
期刊：
影响因子：
6
通讯作者：
Dambrova, Maija
中科院分区：
文献类型：
--
作者：
Liepinsh, Edgars;Makrecka-Kuka, Marina;Dambrova, Maija
酰基肉碱积累与能量代谢途径的扰动有关。在这项研究中，我们证明长链（LC）酰基肉碱是参与体内葡萄糖代谢调节的活性代谢物。给喂养的小鼠单剂量施用棕榈酰肉碱 (PC) 会导致明显的胰岛素不敏感、肌肉中葡萄糖的摄取减少以及血糖水平升高。 LC 酰基肉碱含量增加通过损害 Akt Ser473 磷酸化诱导胰岛素抵抗。使用缓释渗透微型泵长期给予 PC 会引起明显的高胰岛素血症、胰岛素抵抗和葡萄糖耐受不良，这表明 LC 酰基肉碱的永久积累可以加速胰岛素抵抗的进展。酰基肉碱含量的降低显着改善了饮食诱导的葡萄糖不耐受小鼠模型的葡萄糖耐量。总之，我们表明酰基肉碱含量的生理增加确保了从进食状态向禁食状态的转变，从而限制禁食状态下的葡萄糖代谢。在进食状态下，胰岛素无法抑制 LC 酰基肉碱的产生，从而导致葡萄糖摄取和代谢紊乱。降低酰基肉碱含量可能是提高胰岛素敏感性的有效策略。 (c) 2017 年生物因子，43(5):718-730，2017 年
Acylcarnitine accumulation has been linked to perturbations in energy metabolism pathways. In this study, we demonstrate that long-chain (LC) acylcarnitines are active metabolites involved in the regulation of glucose metabolism in vivo. Single-dose administration of palmitoylcarnitine (PC) in fed mice induced marked insulin insensitivity, decreased glucose uptake in muscles, and elevated blood glucose levels. Increase in the content of LC acylcarnitine induced insulin resistance by impairing Akt phosphorylation at Ser473. The long-term administration of PC using slow-release osmotic minipumps induced marked hyperinsulinemia, insulin resistance, and glucose intolerance, suggesting that the permanent accumulation of LC acylcarnitines can accelerate the progression of insulin resistance. The decrease of acylcarnitine content significantly improved glucose tolerance in a mouse model of diet-induced glucose intolerance. In conclusion, we show that the physiological increase in content of acylcarnitines ensures the transition from a fed to fasted state in order to limit glucose metabolism in the fasted state. In the fed state, the inability of insulin to inhibit LC acylcarnitine production induces disturbances in glucose uptake and metabolism. The reduction of acylcarnitine content could be an effective strategy to improve insulin sensitivity. (c) 2017 BioFactors, 43(5):718-730, 2017