A negative regulatory pathway of GLUT4 trafficking in adipocyte: new function of RIP140 in the cytoplasm via AS160

Cell Metab. 2009 Dec;10(6):516-23. doi: 10.1016/j.cmet.2009.09.012.


Receptor-interacting protein 140 (RIP140), a nuclear receptor corepressor, is important for lipid and glucose metabolism. In adipocytes, RIP140 can be phosphorylated by protein kinase C epsilon (PKCvarepsilon), followed by arginine methylation, and exported to the cytoplasm. This study demonstrates for the first time a cytoplasmic function for RIP140: to counteract insulin-stimulated glucose transporter 4 (GLUT4) membrane partitioning and glucose uptake in adipocytes. Cytoplasmic RIP140 interacts with the Akt substrate AS160, thereby impeding AS160 phosphorylation by Akt; this in turn reduces GLUT4 trafficking. This signal transduction pathway can be recapitulated in the epididymal adipocytes of diet-induced obese mice: nuclear PKCvarepsilon is activated, cytoplasmic RIP140 increases, and GLUT4 trafficking and glucose uptake are reduced. The data reveal a new, cytoplasmic function for RIP140 as a negative regulator of GLUT4 trafficking and glucose uptake, and shed insight into the regulation of basal and insulin-stimulated glucose disposal by a nuclear-initiated counteracting mechanism.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adipocytes / metabolism*
  • Animals
  • Cell Line
  • Cytoplasm / metabolism
  • Down-Regulation
  • GTPase-Activating Proteins / metabolism*
  • Glucose / metabolism
  • Glucose Transporter Type 4 / metabolism*
  • Mice
  • Mice, Obese
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Interacting Protein 1
  • Protein Kinase C-epsilon / metabolism
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Subcutaneous Fat / metabolism


  • Adaptor Proteins, Signal Transducing
  • GTPase-Activating Proteins
  • Glucose Transporter Type 4
  • Nuclear Proteins
  • Nuclear Receptor Interacting Protein 1
  • Tbc1d4 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C-epsilon
  • Glucose