Assisted Reproductive Technologies Predispose to Insulin Resistance and Obesity in Male Mice Challenged With a High-Fat Diet
Assisted Reproductive Technologies Predispose to Insulin Resistance and Obesity in Male Mice Challenged With a High-Fat Diet
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DOI：
10.1210/en.2016-1475
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发表时间：
2017-05-01
期刊：
影响因子：
4.8
通讯作者：
Rexhaj, Emrush
中科院分区：
文献类型：
--
作者：
Cerny, David;Sartori, Claudio;Rexhaj, Emrush
辅助生殖技术(ART)改变了小鼠和人类的葡萄糖稳态，但其潜在的机制尚不完全清楚。ART通过内皮型一氧化氮合酶(ENOS)基因的表观遗传改变导致内皮功能障碍和动脉高压。在eNOS缺陷小鼠中，胰岛素抵抗与肌肉血流和底物输送的胰岛素刺激受损以及骨骼肌固有葡萄糖摄取缺陷有关。因此，我们评估了8周内喂养正常饲料(NC)或高脂饮食(HFD)的雄性ART和对照组小鼠的葡萄糖耐量、胰岛素敏感性(正常血糖钳夹)、体内胰岛素对肌肉血流的刺激以及体外肌肉葡萄糖摄取。在NC喂养的动物中，葡萄糖耐量和胰岛素敏感性是相似的。然而，当接受高脂饮食刺激时，ART小鼠出现了过度肥胖、空腹高胰岛素血症和高血糖，并且胰岛素刺激的葡萄糖利用率比对照组低20%(稳态葡萄糖输注率，51.3vs64.0+/-10.8 mg/kg/min，P=0.012)。ART诱导的胰岛素抵抗与缺陷的胰岛素刺激肌肉血流有关，而骨骼肌固有的葡萄糖摄取是正常的。总而言之，ART诱导的内皮功能障碍，当受到代谢应激的挑战时，会促进葡萄糖耐量异常和胰岛素抵抗。类似的机制可能有助于ART诱导的人类代谢表型的改变。
Assisted reproductive technology (ART) alters glucose homeostasis in mice and humans, but the underlying mechanisms are incompletely understood. ART induces endothelial dysfunction and arterial hypertension by epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene. In eNOS-deficient mice, insulin resistance is related to impaired insulin stimulation of muscle blood flow and substrate delivery and defective intrinsic skeletal muscle glucose uptake. We therefore assessed glucose tolerance, insulin sensitivity (euglycemic clamp), insulin stimulation of muscle blood flow in vivo, and muscle glucose uptake in vitro in male ART and control mice fed a normal chow (NC) or challenged with a high-fat diet (HFD) during 8 weeks. Glucose tolerance and insulin sensitivity were similar in NC-fed animals. When challenged with a HFD, however, ART mice developed exaggerated obesity, fasting hyperinsulinemia and hyperglycemia, and a 20% lower insulin-stimulated glucose utilization than did control mice (steady-state glucose infusion rate (GIR), 51.3 +/- 7.3 vs 64.0 +/- 10.8 mg/kg/min, P = 0.012). ART-induced insulin resistance was associated with defective insulin stimulation of muscle blood flow, whereas intrinsic skeletal muscle glucose uptake was normal. In conclusion, ART-induced endothelial dysfunction, when challenged with a metabolic stress, facilitates glucose intolerance and insulin resistance. Similar mechanisms may contribute to ART-induced alterations of the metabolic phenotype in humans.