Leptin Exacerbates Sepsis-Mediated Morbidity and Mortality

Abstract

The adipose-derived hormone leptin is well known for its contribution to energy metabolism and satiety signaling in the hypothalamus. Previous studies suggested that obesity is an independent risk factor for sepsis morbidity and mortality, and it is associated with elevated baseline levels of circulating leptin in normal, nonseptic patients. In mouse endotoxemia and cecal ligation puncture models of sepsis, we observed elevated levels of leptin and soluble leptin receptor (sLR). Exogenously administered leptin increased mortality in endotoxemia and cecal ligation puncture models and was associated with increased expression of adhesion and coagulation molecules, macrophage infiltration into the liver and kidney, and endothelial barrier dysfunction. Conversely, longform leptin receptor-deficient mice were protected from sepsis morbidity and mortality and had less endothelial dysfunction. Furthermore, an in vitro study revealed that leptin-induced endothelial dysfunction is likely mediated, at least in part, by monocytes. Moreover, administration of an sLR conferred a survival benefit. Human septic patients have increased circulating sLR concentrations, which were correlated with disease severity indices. Together, these data support a pathogenic role for leptin signaling during sepsis.

Adipocytokines in Severe Sepsis and Septic Shock

“…These results are in conflict with observations from other investigators. Shapiro et al reported a decrease in survival rates after application of exogenous leptin in murine sepsis models, whereas leptin-receptor deficient mice showed a better outcome with higher survival rates [60]. Despite the strong evidence that leptin takes part in the cell-mediated immunity response and in cytokine crosstalk [69] additional studies for clearing the role of leptin and its receptors in sepsis and SIRS are warranted.…”

“…Moreover, it activates the production of proinflammatory cytokines in cultured monocytes, protects monocytes against apoptosis and influences RNA metabolism. The leptin-receptor itself is similar to members of the class I cytokine family and exists in six isoforms [60].…”

Hormonal Therapies in Severe Sepsis

“…There is evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. Human septic patients have evidence of increased circulating leptin concentrations which correlate with severity of illness, and hence it has been postulated that leptin may play a critical role in the pathogenesis of sepsis-associated multi-organ dysfunction [90]. It has also been suggested that elevated leptin levels may aid in distinguishing between sepsis and non-infectious SIRS [91].…”

Serum Leptin is Decreased Thirty Days after Surgery

“…The leptin production is mainly stimulated by the cytokines TNF α, IL 6, and IL 1β [9] leading to a rapid increase in leptin concentrations. Increased leptin levels are reported in a number of acute inflammatory conditions such as infections and sepsis but also in more chronic disorders such as rheumatoid arthritis, diabetes and atherosclerosis [10][11][12][13][14].…”