Regulation of white and brown adipocyte differentiation by RhoGAP DLC1

PLoS One. 2017 Mar 30;12(3):e0174761. doi: 10.1371/journal.pone.0174761. eCollection 2017.


Adipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified Dlc1 as a super-enhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPARγ, the master regulator of adipogenesis. We further observed that Dlc1 expression increases during differentiation, and knockdown of Dlc1 by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of Dlc1 in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. Dlc1-/- knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPARγ binds to the promoter of Dlc1 gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPARγ and Rho pathways.

MeSH terms

  • Adipocytes, Brown / cytology*
  • Adipocytes, Brown / metabolism*
  • Adipocytes, White / cytology*
  • Adipocytes, White / metabolism*
  • Adipogenesis / genetics
  • Adipogenesis / physiology
  • Blotting, Western
  • Calorimetry, Indirect
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Humans
  • Oxygen Consumption / genetics
  • Oxygen Consumption / physiology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • RNA, Small Interfering / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • DLC1 protein, human
  • GTPase-Activating Proteins
  • PPAR gamma
  • RNA, Small Interfering
  • Tumor Suppressor Proteins
  • rho GTPase-activating protein

Grant support

This work was supported by the intramural funding from the Agency for Science, Technology and Research (A*STAR) of Singapore to FX. Funding for the open-access charge was provided by A*STAR of Singapore. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.