Abstract 6255: Adiponectin Deficiency Profoundly Exacerbates Sepsis-Related Mortality through Endothelial Activation: A Novel Mechanistic Link between Adiposity and Sepsis

INTRODUCTION: Sepsis is a multifactorial, and often fatal disorder, characterized by widespread inflammation with resultant endothelial activation. Adiposity and diabetes are strong negative predictors of sepsis related cardiovascular dysregulation and mortality, however, the mechanisms remain unclear. We postulated that alterations in adipokine biology, particularly adiponectin, are essential modulators of survival and endothelial activation in sepsis. METHODS AND RESULTS: We evaluated both loss-of-function (adiponectin gene-deficient mice) and subsequent gain-of-function (recombinant adiponectin reconstitution) strategies in two well-established inflammatory models, cecal ligation perforation (CLP) and thioglyocollate-induced peritonitis. Adipoq −/− mice, subjected to CLP, exhibited a profound (~8 fold) reduction in survival compared to their wild-type Adipoq −/− littermates after 48 hours. Furthermore, compared to wild-type controls, thioglycollate challenge resulted in a markedly greater influx of peritoneal neutrophils in Adipoq −/− mice accompanied by an excess production of key chemoattractant cytokines (IL-12p70, TNFalpha, MCP-1 and IL-6) and upregulation of aortic endothelial adhesion molecule expression, VCAM-1 and ICAM-1. Importantly, all of these effects were blunted by recombinant total adiponectin administration given three days prior to thioglycollate challenge. The protective effects of adiponectin were largely ascribed to higher order adiponectin oligomers, since administration of recombinant trimeric adiponectin did not attenuate endothelial adhesion molecule expression in thioglycollate-challenged Adipoq −/− mice. CONCLUSIONS: These data suggest a critical role of adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and suggest one of the first mechanistic links between adiposity and sepsis related death.