Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Obes Facts. 2018;11(2):93-108. doi: 10.1159/000486962. Epub 2018 Apr 10.
We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level.
We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student’s t-test for independent samples was applied and effect sizes using Cohen’s d were calculated.
In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 ( Cap1 (150Arg; d = 7.48), Mapk1 (343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)).
The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.
我们旨在确定人类 SH2B1 变体对调节能量稳态的主要调节剂瘦素和胰岛素信号在 RNA 水平上的影响。
我们分析了七个 SH2B1 变体（Arg67Cys、Lys150Arg、Thr175Ala、Thr343Met、Thr484Ala、Ser616Pro 和 Pro689Leu）的罕见等位基因在胰岛素或瘦素细胞刺激下的表达情况。其中两个是在我们自己的突变筛选中发现的，其他的则被预测为有害或作为对照。这些变体在同源的小鼠下丘脑细胞系统中进行了分析。测量下游基因表达的变化。应用了独立样本的 Student’s t 检验，并计算了 Cohen’s d 的效应大小。
在涉及瘦素（JAK/STAT 或 AKT）信号通路的 54 个分析基因中，有 34 个基因的表达发生了名义上的变化。三个基因的表达显著增加（p 值≤0.001：Gbp2b（67Cys；d=25.11）、Irf9（689Leu；d=44.65）和 Isg15（150Arg；d=20.35））。在胰岛素信号通路中分析的 32 个基因中，有 10 个基因的表达名义上发生了变化（p≤0.05），其中 3 个基因的 p 值≤0.01（Cap1（150Arg；d=7.48）、Mapk1（343Met；d=-6.80）和 Sorbs1（689Leu；d=7.82））。
瘦素（JAK/STAT 或 AKT）信号通路中基因表达的增加表明，人类 SH2B1 突变的主要作用模式可能影响瘦素信号而不是胰岛素信号。
