Leptin Receptor Signaling Regulates Protein Synthesis Pathways and Neuronal Differentiation in Pluripotent Stem Cells

The role of leptin receptor (OB-R) in linking pluripotency with growth, development, and the consequences on the progression of metabolic disease is poorly understood. Using a global unbiased proteomics approach we report that embryonic fibroblasts (MEFs) carrying db/db mutation exhibited metabolic abnormalities, while their reprogrammed induced pluripotent stem cells (iPSCs) demonstrated alterations in the expression of proteins involved in embryonic development. An upregulation in the expression of eukaryotic translation initiation factor4e (eIF4e) and Stat3 binding to the eIF4e promoter was supported by enhanced protein synthesis in mutant iPSCs. Directed differentiation of db/db iPSCs towards the neuronal lineage showed defects compared to controls. Gene editing to correct point mutation in db/db iPSCs using CRISPR/Cas9, restored the metabolic defects, expression of neuronal markers, and protein synthesis as corroborated by RNAseq analyses. These data imply a direct role for OB-R in regulating metabolic properties in embryonic fibroblasts and key developmental pathways in iPSCs.