Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance

Sci Adv. 2016 Mar 25;2(3):e1501332. doi: 10.1126/sciadv.1501332. eCollection 2016 Mar.


Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

Keywords: Toll-like receptor-9; adipose tissue; cell-free DNA; inflammation; insulin resistance; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Adult
  • Aged
  • Animals
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Cell Communication
  • DNA / blood
  • DNA / metabolism*
  • Female
  • Gene Deletion
  • Gene Expression
  • Humans
  • Insulin Resistance / genetics
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / pathology
  • Panniculitis / genetics
  • Panniculitis / metabolism*
  • Panniculitis / pathology
  • Signal Transduction
  • Toll-Like Receptor 9 / antagonists & inhibitors
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / metabolism


  • Toll-Like Receptor 9
  • DNA