Department of Molecular Immune and Cell Biology, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany.
Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany.
Sci Rep. 2019 Mar 5;9(1):3442. doi: 10.1038/s41598-019-40231-3.
Insulin plays a central role in regulating metabolic homeostasis and guanine-nucleotide exchange factors of the cytohesin family have been suggested to be involved in insulin signal transduction. The Drosophila homolog of cytohesin-3, steppke, has been shown to be essential for insulin signaling during larval development. However, genetic evidence for the functional importance of cytohesin-3 in mammals is missing. We therefore analyzed the consequences of genetic cytohesin-3-deficiency on insulin signaling and function in young and aged mice, using normal chow or high-fat diet (HFD). Insulin-receptor dependent signaling events are significantly reduced in liver and adipose tissue of young cytohesin-3-deficient mice after insulin-injection, although blood glucose levels and other metabolic parameters remain normal in these animals. Interestingly, however, cytohesin-3-deficient mice showed a reduced age- and HFD-induced weight gain with a significant reduction of body fat compared to wild-type littermates. Furthermore, cytohesin-3-deficient mice on HFD displayed no alterations in energy expenditure, but had an increased lipid excretion instead, as well as a reduced expression of genes essential for bile acid synthesis. Our findings show for the first time that an intact cyth3 locus is required for full insulin signaling in mammals and might constitute a novel therapeutic target for weight reduction.
胰岛素在调节代谢稳态中起着核心作用，细胞松弛素家族的鸟嘌呤核苷酸交换因子已被认为参与胰岛素信号转导。果蝇细胞松弛素-3 的同源物 steppke 在幼虫发育过程中对胰岛素信号至关重要。然而，细胞松弛素-3 在哺乳动物中的功能重要性的遗传证据尚缺乏。因此，我们使用普通饲料或高脂肪饮食（HFD）分析了年轻和老年小鼠中细胞松弛素-3 缺失对胰岛素信号和功能的影响。尽管这些动物的血糖水平和其他代谢参数保持正常，但在接受胰岛素注射后，年轻的细胞松弛素-3 缺陷型小鼠的肝脏和脂肪组织中胰岛素受体依赖性信号事件显著减少。有趣的是，与野生型同窝仔相比，细胞松弛素-3 缺陷型小鼠的体重增长随着年龄的增长和 HFD 的诱导而减少，体脂肪减少。此外，HFD 喂养的细胞松弛素-3 缺陷型小鼠的能量消耗没有改变，但脂质排泄增加，胆汁酸合成所必需的基因表达减少。我们的研究结果首次表明，完整的 cyth3 基因座对于哺乳动物中完整的胰岛素信号转导是必需的，并且可能成为减肥的新治疗靶点。
