Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality

Abstract

Sepsis is a multifactorial, and often fatal, disorder typically characterized by widespread inflammation and immune activation with resultant endothelial activation. In the present study, we postulated that the adipokine adiponectin serves as a critical modulator of survival and endothelial activation in sepsis. To this aim, 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 ( approximately 8-fold) reduction in survival compared with their wild-type Adipoq(+/+) littermates after 48 h. Furthermore, compared with 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 VCAM-1 and ICAM-1 expressions. Importantly, all of these effects were blunted by recombinant total adiponectin administration given 3 days prior to thioglycollate challenge. The protective effects of adiponectin were ascribed largely to higher-order adiponectin oligomers, since administration of recombinant C39A trimeric adiponectin did not attenuate endothelial adhesion molecule expression in thioglycollate-challenged Adipoq(-/-) mice. These data suggest a critical role of adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and a potential mechanistic link between adiposity and increased sepsis.

The effects of LPS-induced endotoxemia on the expression of adiponectin and its receptors in female rats

“…Although it has been reported that APN plays pivotal roles in the regulation of acute inflammatory responses [8][9][10][11][12][13][14][15][16][17], the changes in the expression levels of endogenous APN and AdipoR during such conditions have not been fully elucidated, especially in females. Therefore, the present study mainly focused on the effects of LPS-induced sepsis on APN and AdipoR expression in peripheral and central tissues in female rats.…”

“…On the other hand, increased serum APN levels are associated with mortality in patients that suffer respiratory failure [9]. In polymicrobial-or lipopolysaccharide (LPS)-induced septic conditions, APN knockout (KO) and obese APNdeficient rodents display significantly higher mortality rates than wild-type (WT) controls [10][11][12][13]. Similarly, it was found that polymicrobial-induced sepsis caused worse hepatic injuries in APN KO mice than in the WT serum, hepatic, and hypothalamic levels were also measured.…”

Endocrine, Metabolic, and Morphologic Alterations of Adipose Tissue During Critical Illness*

“…Interestingly, adiponectin knockout mice suffer from substantially increased mortality after cecal ligation and puncture-induced sepsis or thioglyocollateinduced peritonitis, largely attributable to impaired immune and endothelial function (90). Treatment with adiponectin prior to the insult blunted these effects (90).…”

Adiponectin suppresses inflammatory responses at the early phase of atherosclerosis in hyperglycemic rats

“…adiponectin Ko mice infected by ad-aPn prior to vascular injury exhibited a 2-to 3-fold increase in serum levels of adiponectin, leading to less intimal thickening (18). adipo (-/-) mice exhibited an excess production of key chemoattractant cytokines and increased expression of the aortic endothelial adhesion molecules VcaM-1 and ICAM-1 (19). Here, for the first time, we demonstrated that the adenovirus-mediated increase of serum adiponectin inhibited the expression of icaM-1, VcaM-1 and McP-1 in aortic tissue, and suppressed the levels of sicaM-1 and crP in serum in hyperglycemic rats.…”