Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

Cell Rep. 2017 Oct 24;21(4):1021-1035. doi: 10.1016/j.celrep.2017.09.091.


Lower adipose-ChREBP and de novo lipogenesis (DNL) are associated with insulin resistance in humans. Here, we generated adipose-specific ChREBP knockout (AdChREBP KO) mice with negligible sucrose-induced DNL in adipose tissue (AT). Chow-fed AdChREBP KO mice are insulin resistant with impaired insulin action in the liver, muscle, and AT and increased AT inflammation. HFD-fed AdChREBP KO mice are also more insulin resistant than controls. Surprisingly, adipocytes lacking ChREBP display a cell-autonomous reduction in insulin-stimulated glucose transport that is mediated by impaired Glut4 translocation and exocytosis, not lower Glut4 levels. AdChREBP KO mice have lower levels of palmitic acid esters of hydroxy stearic acids (PAHSAs) in serum, and AT. 9-PAHSA supplementation completely rescues their insulin resistance and AT inflammation. 9-PAHSA also normalizes impaired glucose transport and Glut4 exocytosis in ChREBP KO adipocytes. Thus, loss of adipose-ChREBP is sufficient to cause insulin resistance, potentially by regulating AT glucose transport and flux through specific lipogenic pathways.

Keywords: ChREBP; Glut4 trafficking; PAHSA; adipose tissue inflammation; adipose-carbohydrate response element binding protein; de novo lipogenesis; glucose transport; palmitic acid hydroxy stearic acid; systemic insulin resistance.

MeSH terms

  • 3T3 Cells
  • Adipocytes / metabolism*
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Cells, Cultured
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Insulin Resistance*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Palmitic Acids / blood
  • Stearic Acids / blood
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Glucose Transporter Type 4
  • Mlxipl protein, mouse
  • Nuclear Proteins
  • Palmitic Acids
  • Slc2a4 protein, mouse
  • Stearic Acids
  • Transcription Factors
  • Glucose