PI3K/Akt is involved in brown adipogenesis mediated by growth differentiation factor-5 in association with activation of the Smad pathway

Biochem Biophys Res Commun. 2014 Jul 18;450(1):255-60. doi: 10.1016/j.bbrc.2014.05.108. Epub 2014 Jun 2.


We have previously demonstrated promotion by growth differentiation factor-5 (GDF5) of brown adipogenesis for systemic energy expenditure through a mechanism relevant to activating the bone morphological protein (BMP) receptor/mothers against decapentaplegic homolog (Smad)/peroxisome proliferator-activated receptor gamma co-activator 1α (PGC-1α) pathway. Here, we show the involvement of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in brown adipogenesis mediated by GDF5. Overexpression of GDF5 in cells expressing adipocyte protein-2 markedly accelerated the phosphorylation of Smad1/5/8 and Akt in white and brown adipose tissues. In brown adipose tissue from heterozygous GDF5(Rgsc451) mutant mice expressing a dominant-negative (DN) GDF5 under obesogenic conditions, the basal phosphorylation of Smad1/5/8 and Akt was significantly attenuated. Exposure to GDF5 not only promoted the phosphorylation of both Smad1/5/8 and Akt in cultured brown pre-adipocytes, but also up-regulated Pgc1a and uncoupling protein-1 expression in a manner sensitive to the PI3K/Akt inhibitor Ly294002 as well as retroviral infection with DN-Akt. GDF5 drastically promoted BMP-responsive luciferase reporter activity in a Ly294002-sensitive fashion. Both Ly294002 and DN-Akt markedly inhibited phosphorylation of Smad5 in the nuclei of brown pre-adipocytes. These results suggest that PI3K/Akt signals play a role in the GDF5-mediated brown adipogenesis through a mechanism related to activation of the Smad pathway.

Keywords: Brown adipocytes; GDF5; PGC-1a; PI3K/Akt pathway; Smad5; UCP1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipogenesis / physiology*
  • Adipose Tissue, Brown / cytology*
  • Adipose Tissue, Brown / physiology*
  • Animals
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Growth Differentiation Factor 5 / metabolism*
  • Mice
  • Mice, Transgenic
  • Oncogene Protein v-akt / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Signal Transduction / physiology
  • Smad Proteins / metabolism*


  • Gdf5 protein, mouse
  • Growth Differentiation Factor 5
  • Smad Proteins
  • Phosphatidylinositol 3-Kinases
  • Oncogene Protein v-akt