leptin and Bacteremia

Topics: Bacteremia; Epilepsy; History, 20th Century; Humans; Intelligence Tests; Leptin; United States

Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency in ob/ob mice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.

Topics: Animals; Bacteremia; Brain; Disease Models, Animal; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroimmunomodulation; Neutrophils; Random Allocation; Receptors, Leptin; Sepsis

The adipocyte-derived hormone leptin is an important regulator of appetite and energy expenditure and is now appreciated for its ability to control innate and adaptive immune responses. We have reported previously that the leptin-deficient ob/ob mouse exhibited increased susceptibility to the Gram-negative bacterium Klebsiella pneumoniae. In this report we assessed the impact of chronic leptin deficiency, using ob/ob mice, on pneumococcal pneumonia and examined whether restoring circulating leptin to physiological levels in vivo could improve host defences against this pathogen. We observed that ob/ob mice, compared with wild-type (WT) animals, exhibited enhanced lethality and reduced pulmonary bacterial clearance following Streptococcus pneumoniae challenge. These impairments in host defence in ob/ob mice were associated with elevated levels of lung tumour necrosis factor (TNF)-alpha, macrophage inflammatory peptide (MIP)-2 [correction added after online publication 28 September 2007: definition of MIP corrected], prostaglandin E(2) (PGE(2)), lung neutrophil polymorphonuclear leukocyte (PMN) counts, defective alveolar macrophage (AM) phagocytosis and PMN killing of S. pneumoniae in vitro. Exogenous leptin administration to ob/ob mice in vivo improved survival and greatly improved pulmonary bacterial clearance, reduced bacteraemia, reconstituted AM phagocytosis and PMN H(2)O(2) production and killing of S. pneumoniae in vitro. Our results demonstrate, for the first time, that leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia. Further investigations are warranted to determine whether there is a potential therapeutic role for this adipokine in immunocompromised patients.

Topics: Animals; Bacteremia; Cytokines; Disease Susceptibility; Drug Evaluation, Preclinical; Female; Hydrogen Peroxide; Leptin; Leukocyte Count; Lung; Mice; Mice, Inbred C57BL; Mice, Obese; Neutrophil Infiltration; Phagocytosis; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Survival Analysis

High levels of serum leptin (LPT) were reported in adult patients with sepsis and a protective role was suggested. LPT was determined in sera from 55 children with severe sepsis at admission (0 h), 6, 24 and 48 h. LPT levels were higher at 0 h than at 24 h (2.80 vs 1.61 ng/ml; p = 0.009) and a negative correlation was found with IL-13 (p = 0.009), and granulocyte counts (p = 0.035), but not with other factors. Infants younger than 12 mo of age had higher LPT levels than older infants (5.88 vs 2.38 ng/ml; p = 0.0005). The increase in LPT levels was higher in non-survivor patients than in survivors, with a maximum difference at 24 h (5.30 vs 1.45 ng/ml; p = 0.0042). However, LPT levels were not associated with shock, multiorgan failure or the severity score. Children who died showed higher percentiles of weight than survivors (p = 0.025). A subgroup with higher LPT (> Pc75) included mainly patients with weight > Pc50 (p = 0.0065), low IL-13 levels (p = 0.007) and low granulocyte counts (p = 0.013), Neisseria meningitidis B being the most frequently isolated germ (p = 0.022).. Using a model of severe infection, mainly meningococcal, in young children (median 3 y 6 mo old), it was not possible to confirm previous results in adults. A general protective role for LPT in sepsis seems unlikely.

Topics: Adolescent; Bacteremia; Biomarkers; Body Weight; Child; Child, Preschool; Critical Care; Enzyme-Linked Immunosorbent Assay; Female; Humans; Infant; Infant, Newborn; Intensive Care Units, Pediatric; Leptin; Male; Probability; Prognosis; Prospective Studies; Sensitivity and Specificity; Severity of Illness Index; Statistics, Nonparametric; Survival Analysis

Leptin production is increased in rodents by administration of endotoxin or cytokines. To investigate whether circulating leptin is related to cytokine release and survival in human sepsis, plasma concentrations of leptin, interleukin (IL)-6, IL-1beta, tumor necrosis factor (TNF)-alpha, soluble TNF receptor type I, IL-1 receptor antagonist (IL-1ra), and the inflammatory modulator IL-10 were measured as soon as severe sepsis (n=28) or septic shock (n=14) developed and every 6 h for 24 h. Patients with sepsis or septic shock had leptin concentrations 2.3- and 4.2-fold greater, respectively, than the control group. There was an independent association for leptin with IL-1ra and IL-10 in both patient groups. By discriminant analysis, leptin and IL-6 were independent predictors of death. These findings suggest that increases in leptin levels may be a host defense mechanism during sepsis.

Topics: Analysis of Variance; Bacteremia; Biomarkers; Confidence Intervals; Critical Illness; Cytokines; Discriminant Analysis; Humans; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-6; Leptin; Predictive Value of Tests; Prognosis; Proteins; Receptors, Interleukin-1; Receptors, Leptin; Receptors, Tumor Necrosis Factor; Shock, Septic; Sialoglycoproteins; Survival Rate; Survivors