BACKGROUND: Abnormal fatty acid metabolism is an important feature in the mechanisms of insulin resistance and beta-cell dysfunction. Carnitine palmitoyltransferase-1a (CPT-1a, liver isoform) plays a pivotal role in the regulation of mitochondrial fatty acid oxidation. We investigated the role of CPT-1a in the development of impaired glucose tolerance using a mouse model for CPT-1a deficiency when challenged by either a high-carbohydrate (HCD) or a high-fat diet (HFD) for a total duration of up to 46 weeks. METHODS: Insulin sensitivity and glucose tolerance were assessed in heterozygous CPT-1a deficient (CPT-1a+/-) male mice after being fed either a HCD or a HFD for durations of 28 weeks and 46 weeks. Both glucose and insulin tolerance tests were used to investigate beta-cell function and insulin sensitivity. Differences in islet insulin content and hepatic steatosis were evaluated by morphological analysis. RESULTS: CPT-1a+/- mice were more insulin sensitive than CPT-1a+/+ mice when fed either HCD or HFD. The increased insulin sensitivity was associated with an increased expression of Cpt-1b (muscle isoform) in liver, as well as increased microvesicular hepatic steatosis compared to CPT-1a+/+ mice. CPT-1a+/- mice were more glucose tolerant than CPT-1a+/+ mice when fed the HCD, but there was no significant difference when fed HFD. Moreover, CPT-1a+/- mice fed HFD or HCD had fewer and smaller pancreatic islets than CPT-1a+/+ mice. CONCLUSIONS: CPT-1a deficiency preserved insulin sensitivity when challenged by long term feeding of either diet. Furthermore, CPT-1a deficient mice had distinct phenotypes dependent on the diet fed demonstrating that both diet and genetics collectively play a role in the development of impaired glucose tolerance.

中文翻译：

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高脂肪或高碳水化合物饮食对杂合肉碱棕榈酰转移酶-1a (CPT-1a) 缺乏症小鼠葡萄糖耐量的长期影响：饮食对 CPT1a 缺乏症小鼠的影响。

背景：脂肪酸代谢异常是胰岛素抵抗和 β 细胞功能障碍机制中的一个重要特征。肉碱棕榈酰转移酶-1a（CPT-1a，肝同种型）在调节线粒体脂肪酸氧化中起关键作用。我们使用 CPT-1a 缺乏症小鼠模型研究了 CPT-1a 在糖耐量受损发展中的作用，当受到高碳水化合物 (HCD) 或高脂肪饮食 (HFD) 的挑战时，总持续时间为到 46 周。方法：在喂食 HCD 或 HFD 28 周和 46 周后，在杂合 CPT-1a 缺陷 (CPT-1a+/-) 雄性小鼠中评估胰岛素敏感性和葡萄糖耐量。葡萄糖和胰岛素耐受性测试均用于研究 β 细胞功能和胰岛素敏感性。通过形态学分析评估胰岛胰岛素含量和肝脂肪变性的差异。结果：当喂食 HCD 或 HFD 时，CPT-1a+/- 小鼠比 CPT-1a+/+ 小鼠对胰岛素更敏感。与 CPT-1a+/+ 小鼠相比，胰岛素敏感性增加与肝脏中 Cpt-1b（肌肉同种型）表达增加以及微泡性肝脂肪变性增加有关。当喂食 HCD 时，CPT-1a+/- 小鼠比 CPT-1a+/+ 小鼠更耐葡萄糖，但喂食 HFD 时没有显着差异。此外，与 CPT-1a+/+ 小鼠相比，喂食 HFD 或 HCD 的 CPT-1a+/- 小鼠具有更少和更小的胰岛。结论：当受到任一饮食的长期喂养挑战时，CPT-1a 缺乏可保持胰岛素敏感性。此外，