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

Stem Cell Reports. 2020 Nov 10;15(5):1067-1079. doi: 10.1016/j.stemcr.2020.10.001. Epub 2020 Oct 29.

Abstract

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.

Keywords: EIF4E; STAT3; cancer; diabetes; embryonic development; leptin receptor; neuronal lineage; pluripotency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cell Differentiation
  • Cell Lineage
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Fibroblasts / metabolism
  • Gene Editing
  • Gene Expression Regulation, Developmental
  • Induced Pluripotent Stem Cells / metabolism*
  • Metabolome
  • Mice
  • Mice, Knockout
  • Neurogenesis
  • Protein Biosynthesis*
  • Proteins
  • Proteomics
  • Receptors, Leptin / genetics
  • Receptors, Leptin / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*

Substances

  • Eukaryotic Initiation Factor-4E
  • Proteins
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • eIF4E protein, mouse