Adipocyte release of nucleosides contributes to obesity-associated inflammation

Obese adipose tissue drives inflammation through several mechanisms. Extracellular nucleosides can induce macrophage inflammation through the activation of toll-like and purinergic receptors. The present study quantified nucleoside release from adipocytes and adipose tissue. Cultured mouse adipocytes released many nucleosides used in RNA/DNA. Adipose tissue from obese mice released more nucleosides than that from control non-obese mice, resulting in higher interstitial fluid concentrations. Consistent with the mouse study, human adipose tissue also showed significant release of adenosine/deoxyadenosine, guanosine/deoxyguanosine, and uridine ex vivo. Adipocytes release nucleosides in part through the equilibrative nucleoside transporter 1 (ENT1), and this release induces macrophage TNFα and IL-1β expression. Treatment of mice with the ENT1 inhibitor in vivo increased adipose tissue interstitial nucleoside concentrations and cytokine expression. These data uncover a previously unknown phenomenon of adipocyte release of nucleosides, which contribute to adipose tissue inflammation in obesity.