Adiponectin suppresses IκB kinase activation induced by tumor necrosis factor-α or high glucose in endothelial cells:: role of cAMP and AMP kinase signaling

Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-alpha (TNF alpha) and high glucose, activate I kappa B kinase (IKK)beta and reduce the abundance of its substrate, inhibitor of kappa B (I kappa B)alpha, leading to nuclear translocation of the transcription factor NF-kappa B and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKK beta by either TNF alpha or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of I kappa B alpha protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKK beta activity, whereas both pathways were comparably active in suppressing the TNF alpha-induced increase in IKK beta. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNF alpha-and high glucose-mediated IKK beta activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.