Endocrine Abstracts

Adiponectin, an exclusive adipose-derived hormone, circulates at high concentration, and exerts metabolic effects. Adiponectin levels in the circulation correlate negatively with BMI, and low adiponectin concentrations are associated with the low grade inflammation and metabolic dysfunction that accompanies obesity. Adiponectin has been reported to have potent anti-inflammatory activities, and to exert these effects by regulating macrophage function. The mechanism of adiponectin action remains unclear, but a broad effect on expression of pro-inflammatory cytokines has been suggested. Here, we show that prior exposure of primary murine macrophages to adiponectin for as little as 3 h was sufficient to render them tolerant to subsequent exposure to lipopolysaccharide (LPS), with grossly reduced proinflammatory cytokine output. Continued exposure to adiponectin was required to maintain tolerance, with macrophages regaining sensitivity to LPS one day following wash out of adiponectin. Adiponectin-induced cross-tolerisation was mediated through suppression of Toll-like receptor signalling, specifically via induction of negative feedback by the signalling inhibitor A20. Further, adiponectin-induced cross-tolerance was dependent on the kinase GSK3, which was required for induction of A20. Pretreatment with the GSK3 inhibitor SB216763 attenuated adiponectin-induced A20 expression and blocked adiponectin-induced cross-tolerance. Our data suggest that adiponectin’s constant presence in the circulation at high levels (in lean subjects) renders macrophages resistant to pro-inflammatory stimuli for the prevention of prolonged and excessive inflammation.

Declaration of funding

This work was supported by BRC.