Connective Tissue Growth Factor Inhibits Adipocyte Differentiation

Am J Physiol Cell Physiol. 2008 Sep;295(3):C740-51. doi: 10.1152/ajpcell.00333.2007. Epub 2008 Jul 2.

Abstract

Adipocyte differentiation is a key process implicated in the pathogenesis of obesity and insulin resistance. Its regulation is triggered by a cascade of transcription factors, including the CCAAT/enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor-gamma (PPARgamma). Growth factors such as transforming growth factor-beta1 (TGF-beta1) are known to inhibit adipocyte differentiation in vitro, via the C/EBP pathway, and in vivo, but whether a downstream mediator of TGF-beta1, connective tissue growth factor (CTGF), also known as CCN2, has a similar role is unknown. Mouse 3T3-L1 cells were differentiated into adipocytes by using standard methods, and effects and regulation of CTGF were studied. Intervention with recombinant human CTGF during differing stages of differentiation caused an inhibition in the development of the adipocyte phenotype, according to the gene expression of the differentiation markers adiponectin and PPARgamma, as well as suppression of lipid accumulation and expression of the lipogenic enzyme glycerol-3-phosphate dehydrogenase. Whereas CTGF gene expression promptly fell by 90% as 3T3-L1 preadipocytes differentiated into mature adipocytes, CTGF mRNA expression was induced by added TGF-beta1. CTGF applied to cells early in the course of differentiation inhibited total cell protein levels and nuclear localization of the beta-isoform of C/EBP (C/EBP-beta) and, subsequently, total cell C/EBP-alpha levels. CTGF also inhibited the adipocyte differentiation program in primary cultures of mouse preadipocytes. Expression of CTGF mRNA was twofold higher in the central fat depots of mice compared with subcutaneous fat, suggesting a potential role for CTGF in vivo. In summary, these data show that CTGF inhibits the adipocyte differentiation program.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / enzymology
  • Adipocytes / metabolism*
  • Adipogenesis* / genetics
  • Adiponectin / genetics
  • Adiponectin / metabolism
  • Adipose Tissue / enzymology
  • Adipose Tissue / metabolism*
  • Animals
  • Autocrine Communication
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • CCAAT-Enhancer-Binding Protein-beta / metabolism
  • Connective Tissue Growth Factor
  • Glycerolphosphate Dehydrogenase / metabolism
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phenotype
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Adiponectin
  • Adipoq protein, mouse
  • CCAAT-Enhancer-Binding Protein-alpha
  • CCAAT-Enhancer-Binding Protein-beta
  • CCN2 protein, human
  • CCN2 protein, mouse
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • PPAR gamma
  • RNA, Messenger
  • Recombinant Proteins
  • Transforming Growth Factor beta1
  • Connective Tissue Growth Factor
  • Glycerolphosphate Dehydrogenase