Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake
Enhanced susceptibility of Cpt1c knockout mice to glucose intolerance induced by a high-fat diet involves elevated hepatic gluconeogenesis and decreased skeletal muscle glucose uptake
复制标题
Cpt1c 敲除小鼠对高脂饮食引起的葡萄糖不耐受的敏感性增强，涉及肝糖异生作用增强和骨骼肌葡萄糖摄取减少
DOI：
10.1007/s00125-009-1284-0
复制
发表时间：
2009-05-01
期刊：
影响因子：
8.2
通讯作者：
Wu, D.
中科院分区：
文献类型：
--
作者：
Gao, X. F.;Chen, W.;Wu, D.
目的/假设：肉碱棕榈酰转移酶-1 (CPT1)c 是 CPT1 家族中的一种新亚型，专门存在于大脑中。 Cpt1c 敲除 (KO) 小鼠更容易受到高脂饮食 (HFD) 诱导的肥胖的影响。然而，这种表型的潜在机制以及 CPT1c 是否参与饮食诱导的胰岛素抵抗的发病机制的问题尚不清楚。 方法：为了评估 CPT1c 在调节全身葡萄糖稳态中的潜在作用，我们生成了 Cpt1c KO 小鼠，并用 HFD 或标准食物攻击它们。每周评估各组的血糖稳态。结果：HFD喂养8周后，Cpt1c KO小鼠出现了比野生型对照更严重的胰岛素抵抗表型。 Cpt1c KO 小鼠对 HFD 诱导的胰岛素抵抗的易感性增加与肥胖无关。 Cpt1c KO 小鼠的葡萄糖耐量受损可归因于肝脏糖异生作用增强和骨骼肌葡萄糖摄取减少。这些作用与肝脏和肌内脂肪酸氧化和氧化基因表达的减少以及这些组织中三酰甘油含量的升高相关。有趣的是，Cpt1c 缺失引起下丘脑 CPT1a 和 CPT1b 亚型表达和活性的特定升高。我们证明血浆 NEFA 浓度升高是诱导这种代偿效应的机制之一。结论/解释：这些结果进一步确立了 CPT1c 在控制全身葡萄糖稳态和调节下丘脑 Cpt1 亚型表达中的作用。我们确定肝脏和骨骼肌葡萄糖代谢的变化是决定 Cpt1c KO 小鼠表型的重要机制。
Aims/hypothesis:Carnitine palmitoyltransferase-1 (CPT1)c is a novel isoform in the CPT1 family and is found specifically in the brain. Cpt1c knockout (KO) mice are more susceptible to high-fat diet (HFD)-induced obesity. However, the underlying mechanism of this phenotype and the question of whether CPT1c is involved in the pathogenesis of diet-induced insulin resistance are unclear.Methods:To assess the potential role of CPT1c in the regulation of whole-body glucose homeostasis, we generated Cpt1c KO mice and challenged them with HFD or standard chow. Glucose homeostasis of each group was assessed weekly.Results:After 8 weeks of HFD feeding, Cpt1c KO mice developed a phenotype of more severe insulin resistance than that in wild-type controls. The increased susceptibility of Cpt1c KO mice to HFD-induced insulin resistance was independent of obesity. Impaired glucose tolerance in Cpt1c KO mice was attributable to elevated hepatic gluconeogenesis and decreased glucose uptake in skeletal muscle. These effects correlated with decreased hepatic and intramuscular fatty acid oxidation and expression of oxidative genes as well as with elevated triacylglycerol content in these tissues. Interestingly, Cpt1c deletion caused a specific elevation of hypothalamic CPT1a and CPT1b isoform expression and activity. We demonstrated that elevated plasma NEFA concentration is one mechanism via which this compensatory effect is induced.Conclusions/interpretation:These results further establish the role of CPT1c in controlling whole-body glucose homeostasis and in the regulation of hypothalamic Cpt1 isoform expression. We identify changes in hepatic and skeletal muscle glucose metabolism as important mechanisms determining the phenotype of Cpt1c KO mice.