RASSF6 expression in adipocytes is down-regulated by interaction with macrophages

PLoS One. 2013 Apr 23;8(4):e61931. doi: 10.1371/journal.pone.0061931. Print 2013.

Abstract

Macrophage infiltration into adipose tissue is associated with obesity and the crosstalk between adipocytes and infiltrated macrophages has been investigated as an important pathological phenomenon during adipose tissue inflammation. Here, we sought to identify adipocyte mRNAs that are regulated by interaction with infiltrated macrophages in vivo. An anti-inflammatory vitamin, vitamin B6, suppressed macrophage infiltration into white adipose tissue and altered mRNA expression. We identified >3500 genes whose expression is significantly altered during the development of obesity in db/db mice, and compared them to the adipose tissue mRNA expression profile of mice supplemented with vitamin B6. We identified PTX3 and MMP3 as candidate genes regulated by macrophage infiltration. PTX3 and MMP3 mRNA expression in 3T3-L1 adipocytes was up-regulated by activated RAW264.7 cells and these mRNA levels were positively correlated with macrophage number in adipose tissue in vivo. Next, we screened adipose genes down-regulated by the interaction with macrophages, and isolated RASSF6 (Ras association domain family 6). RASSF6 mRNA in adipocytes was decreased by culture medium conditioned by activated RAW264.7 cells, and RASSF6 mRNA level was negatively correlated with macrophage number in adipose tissue, suggesting that adipocyte RASSF6 mRNA expression is down-regulated by infiltrated macrophages in vivo. Finally, this study also showed that decreased RASSF6 expression up-regulates mRNA expression of several genes, such as CD44 and high mobility group protein HMGA2. These data provide novel insights into the biological significance of interactions between adipocytes and macrophages in adipose tissue during the development of obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipocytes / pathology
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism*
  • Adipose Tissue, White / pathology
  • Animals
  • C-Reactive Protein / genetics
  • C-Reactive Protein / metabolism
  • Cell Communication / drug effects
  • Cell Line
  • Cell Movement / drug effects
  • Culture Media, Conditioned / pharmacology
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects
  • HMGA2 Protein / genetics
  • HMGA2 Protein / metabolism
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Matrix Metalloproteinase 3 / genetics
  • Matrix Metalloproteinase 3 / metabolism
  • Mice
  • Mice, Transgenic
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Signal Transduction / drug effects
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Vitamin B 6 / pharmacology

Substances

  • Cd44 protein, mouse
  • Culture Media, Conditioned
  • HMGA2 Protein
  • Hyaluronan Receptors
  • Nerve Tissue Proteins
  • RASSF6 protein, mouse
  • RNA, Messenger
  • Tumor Suppressor Proteins
  • neuronal pentraxin
  • Vitamin B 6
  • C-Reactive Protein
  • Matrix Metalloproteinase 3
  • Mmp3 protein, mouse
  • Monomeric GTP-Binding Proteins

Grant support

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and NA 6634 from the Heart and Stroke Foundation of Canada. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.