The role of leptin receptor (OB-R) signaling in linking pluripotency with growth and development and the consequences of dysfunctional leptin signaling on progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying the db/db mutation exhibit metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) show altered expression of proteins involved in embryonic development. An upregulation in expression of eukaryotic translation initiation factor 4e (Eif4e) and Stat3 binding to the Eif4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs toward the neuronal lineage showed defects. Gene editing to correct the point mutation in db/db iPSCs using CRISPR-Cas9, restored expression of neuronal markers and protein synthesis while reversing the metabolic defects. These data imply a direct role for OB-R in regulating metabolism in embryonic fibroblasts and key developmental pathways in iPSCs.

瘦素受体 (OB-R) 信号在将多能性与生长发育联系起来的作用以及瘦素信号功能失调对代谢疾病进展的后果知之甚少。我们使用全球无偏见的蛋白质组学方法报告携带 db/db 突变的胚胎成纤维细胞 (MEF) 表现出代谢异常，而其重新编程的诱导多能干细胞 (iPSC) 显示参与胚胎发育的蛋白质表达发生改变。真核翻译起始因子 4e ( Eif4e ) 和Stat3与Eif4e结合的表达上调突变体 iPSC 中增强的蛋白质合成支持启动子。db/db iPSCs 向神经元谱系的定向分化显示出缺陷。使用 CRISPR-Cas9 进行基因编辑以纠正 db/db iPSC 中的点突变，恢复神经元标记物的表达和蛋白质合成，同时逆转代谢缺陷。这些数据暗示 OB-R 在调节胚胎成纤维细胞的代谢和 iPSC 的关键发育途径中的直接作用。