Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

J Cell Sci. 2015 Aug 1;128(15):2881-90. doi: 10.1242/jcs.170282. Epub 2015 Jun 11.

Abstract

A better understanding of molecular regulation in adipogenesis might help the development of efficient strategies to cope with obesity-related diseases. Here, we report that CCAAT/enhancer-binding protein (C/EBP) β and C/EBPδ, two crucial pro-adipogenic transcription factors, are controlled at a translational level by serine/threonine kinase 40 (Stk40). Genetic knockout (KO) or knockdown (KD) of Stk40 leads to increased protein levels of C/EBP proteins and adipocyte differentiation in mouse embryonic fibroblasts (MEFs), fetal liver stromal cells, and mesenchymal stem cells (MSCs). In contrast, overexpression of Stk40 abolishes the enhanced C/EBP protein translation and adipogenesis observed in Stk40-KO and -KD cells. Functionally, knockdown of C/EBPβ eliminates the enhanced adipogenic differentiation in Stk40-KO and -KD cells substantially. Mechanistically, deletion of Stk40 enhances phosphorylation of eIF4E-binding protein 1, leading to increased eIF4E-dependent translation of C/EBPβ and C/EBPδ. Knockdown of eIF4E in MSCs decreases translation of C/EBP proteins. Moreover, Stk40-KO fetal livers display an increased adipogenic program and aberrant lipid and steroid metabolism. Collectively, our study uncovers a new repressor of C/EBP protein translation as well as adipogenesis and provides new insights into the molecular mechanism underpinning the adipogenic program.

Keywords: 4E-BP1; Adipogenesis; C/EBP; Stk40; eIF4E.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adaptor Proteins, Signal Transducing
  • Adipogenesis / genetics*
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics*
  • CCAAT-Enhancer-Binding Protein-delta / genetics*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Line
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factors
  • Gene Knockout Techniques
  • Lipid Metabolism / genetics
  • Mice
  • Obesity / genetics
  • Phosphoproteins / metabolism
  • Promoter Regions, Genetic
  • Protein Binding / genetics
  • Protein Biosynthesis / genetics
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • CCAAT-Enhancer-Binding Protein-beta
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Eukaryotic Initiation Factors
  • Phosphoproteins
  • eIF4E protein, mouse
  • CCAAT-Enhancer-Binding Protein-delta
  • Protein Serine-Threonine Kinases
  • Stk40 protein, mouse