Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs.
AMP-activated protein kinase (AMPK), an energy-sensing enzyme that is activated in response to cellular stress, is a critical signaling molecule for the regulation of multiple metabolic processes. AMPK has recently emerged as an attractive novel target for the treatment of obesity and type 2 diabetes because its activation increases fatty acid oxidation and improves glucose homeostasis. Here we show that pharmacological activation of AMPK by insulin-sensitizing drugs markedly inhibits inducible nitric-oxide synthase (iNOS), a proinflammatory mediator in endotoxic shock and in chronic inflammatory states including obesity-linked diabetes. AMPK-mediated iNOS inhibition was observed in several cell types (myocytes, adipocytes, macrophages) and primarily resulted from post-transcriptional regulation of the iNOS protein. AMPK activation in vivo also blunted iNOS induction in muscle and adipose tissues of endotoxin-challenged rats. Reduction of AMPK expression by small interfering RNA reversed the inhibitory effects of AMPK activators on iNOS expression and nitric oxide production in myocytes. These results indicate that AMPK is a novel anti-inflammatory signaling pathway and thus represents a promising therapeutic target for immune-inflammatory disorders.
Pilon
Geneviève
G
Department of Anatomy and Physiology, and Lipid Research Unit, Laval University Hospital Research Center, 2705 Laurier Boulevard, Sainte-Foy, Québec G1V 4G2, Canada.
Dallaire
Patrice
P
Marette
André
A
D016475:3T3 Cells; D017667:Adipocytes / Q000201:enzymology; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D001483:Base Sequence; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D004789:Enzyme Activation; D007328:Insulin / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000201:enzymology; D018482:Muscle, Skeletal / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016207:Cytokines; D007328:Insulin; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases