目的:我们检验了低睾酮改变间歇性缺氧(IH)对葡萄糖稳态影响的假设,肝脏氧化应激,和雄性小鼠的转录组学特征。
方法:我们使用暴露于常氧(Nx)或IH2周的假手术或睾丸切除(ORX)小鼠。我们进行了空腹胰岛素和葡萄糖耐量测试,并使用HOMA-IR评估了空腹和餐后胰岛素抵抗。肝促氧化剂(NADPH氧化酶-NOX)的活性,抗氧化酶(超氧化物歧化酶,过氧化氢酶,和谷胱甘肽过氧化物酶-SOD,猫,GPx),脂质过氧化(MDA浓度),在餐后条件下测量谷胱甘肽(GSH)的总浓度。mRNA测序和途径富集分析用于鉴定IH和睾酮之间相互作用的潜在肝脏基因。
结果:在假手术小鼠中,IH改善空腹胰岛素敏感性和糖耐量,而IH对ORX小鼠没有影响。在ORX小鼠中,IH诱导餐后高胰岛素血症,胰岛素抵抗,和酶活性的促氧化谱(SOD活性低),而不改变肝MDA和GSH含量。ORX和IH改变了参与氧化还原酶活性的基因的表达,细胞色素依赖性途径,和谷胱甘肽代谢。在ORX-IH小鼠中上调的基因中,含黄素的单加氧酶(FMO)是特别相关的,因为这些是有效的肝脏抗氧化剂,可以帮助预防ORX-IH小鼠的明显氧化应激.
结论:暴露于IH的雄性小鼠体内低水平的睾酮可诱导餐后高胰岛素血症和胰岛素抵抗,并确定肝脏处理IH诱导的氧化应激的机制。
We tested the hypothesis that low testosterone alters the effects of intermittent hypoxia (IH) on glucose homeostasis, hepatic oxidative stress, and transcriptomic profile in male mice.
We used sham-operated or orchiectomized (ORX) mice exposed to normoxia (Nx) or IH for 2 weeks. We performed fasting insulin and glucose tolerance tests and assessed fasting and postprandial insulin resistance with the HOMA-IR. The activity of hepatic prooxidant (NADPH oxidase-NOX), antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase-SOD, Cat, GPx), lipid peroxidation (MDA concentration), and the total concentration of glutathione (GSH) were measured under postprandial conditions. mRNA sequencing and pathway enrichment analyses were used to identify hepatic genes underlying the interactions between IH and testosterone.
In Sham mice, IH improves fasting insulin sensitivity and glucose tolerance, while there are no effects of IH in ORX mice. In ORX mice, IH induces postprandial hyperinsulinemia, insulin resistance, and a prooxidant profile of enzyme activity (low SOD activity) without altering hepatic MDA and GSH content. ORX and IH altered the expression of genes involved in oxidoreductase activities, cytochromes-dependent pathways, and glutathione metabolism. Among the genes upregulated in ORX-IH mice, the flavin-containing monooxygenases (FMO) are particularly relevant since these are potent hepatic antioxidants that could help prevent overt oxidative stress in ORX-IH mice.
Low levels of testosterone in male mice exposed to IH induce post-prandial hyperinsulinemia and insulin resistance and determine the mechanisms by which the liver handles IH-induced oxidative stress.