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

Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 20 February 2007 ; accepted in final form 5 October 2007

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- (TNF) and high glucose, activate IB kinase (IKK)β and reduce the abundance of its substrate, inhibitor of B (IB), leading to nuclear translocation of the transcription factor NF-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 IKKβ by either TNF or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IB protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKβ activity, whereas both pathways were comparably active in suppressing the TNF-induced increase in IKKβ. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNF- and high glucose-mediated IKKβ 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.

inflammation; endothelial dysfunction; insulin resistance; NF-B

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