Evidence of an anti-inflammatory toll-like receptor 9 (TLR 9) pathway in adipocytes

J Endocrinol. 2019 Feb 1;240(2):325-343. doi: 10.1530/JOE-18-0326.


Adipocytes express various pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and actively participate in anti-bacterial and anti-viral host defence. Obesity is associated with adipose tissue PRR expression. The potential role of Toll-like receptor 9 (TLR9) in adipocytes has not yet been investigated. Here, we evaluated TLR9 expression during adipocyte differentiation (AD) of 3T3-L1 adipocytes, in primary murine adipocytes and in different murine and human adipose tissue depots by real-time PCR, immunocytochemistry and immunohistochemistry. TLR9 expression was inhibited using specific siRNA-mediated knockdown, and TLR9 signaling was induced using specific class A, B and C agonistic CpG-oligodeoxynucleotide (ODN) treatment vs ODN controls in 3T3-L1 adipocytes and in primary murine adipocytes from Tlr9wt/wt vs Tlr9-/- mice. We found that TLR9 gene expression is induced during AD and that TLR9 protein is expressed in murine gonadal and human visceral adipocytes. AD depends on intact TLR9 expression. Tlr9-/- mice demonstrate significantly reduced adiponectin serum levels, while siRNA-mediated TLR9 knockdown led to reduced adiponectin mRNA expression in adipocytes. TLR9 ligands (CpG-ODNs) inhibit pro-inflammatory resistin secretion in mature 3T3-L1 adipocytes. Tlr9-/- as compared to Tlr9wt/wt adipocytes exhibit increased resistin and MCP1 secretion and reduced adiponectin secretion into cell culture supernatants, while TLR9 ligands (ODNs) show differential effects in Tlr9-/- vs Tlr9wt/wt primary murine adipocytes. TLR9 expression is significantly increased in visceral compared to subcutaneous adipose tissue depots in non-diabetic obese patients and correlates with systemic resistin levels in a compartment-specific manner. Thus, adipocytic TLR9 is a putative, new protective factor during (obesity-associated) adipose tissue inflammation.

Keywords: CpG; TLR9; adipocyte; adipokine; adipose tissue; inflammation; pattern recognition receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Cell Differentiation / genetics*
  • Cells, Cultured
  • Gene Expression / drug effects
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mice
  • Obesity / genetics
  • Obesity / metabolism
  • Oligodeoxyribonucleotides / pharmacology
  • RNA Interference
  • Resistin / genetics
  • Resistin / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Toll-Like Receptor 9 / agonists
  • Toll-Like Receptor 9 / genetics*
  • Toll-Like Receptor 9 / metabolism


  • CPG-oligonucleotide
  • Oligodeoxyribonucleotides
  • Resistin
  • Toll-Like Receptor 9