Leptin improves pulmonary bacterial clearance and survival in ob/ob mice during pneumococcal pneumonia

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States
Clinical & Experimental Immunology (Impact Factor: 3.04). 12/2007; 150(2):332-9. DOI: 10.1111/j.1365-2249.2007.03491.x
Source: PubMed


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.

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    • "Previously, we reported that obese leptin-deficient ob/ob mice exhibited greater mortality following an intratracheal challenge with either K. pneumoniae or S.pneumoniae [20], [21]. In these studies, greater mortality in the ob/ob mouse was associated with impaired pulmonary bacterial clearance and attenuated alveolar macrophage and neutrophil phagocytosis and killing of bacteria, and the elaboration of reactive oxygen intermediates [22]. "
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    ABSTRACT: In the US and globally, dramatic increases in the prevalence of adult and childhood obesity have been reported during the last 30 years. In addition to cardiovascular disease, type II diabetes, and liver disease, obesity has recently been recognized as an important risk factor for influenza pneumonia. During the influenza pandemic of 2009, obese individuals experienced a greater severity of illness from the H1N1 virus. In addition, obese mice have also been shown to exhibit increased lethality and aberrant pulmonary inflammatory responses following influenza infection. In contrast to influenza, the impact of obesity on bacterial pneumonia in human patients is controversial. In this report, we compared the responses of lean WT and obese CPEfat/fat mice following an intratracheal infection with Streptococcus pneumoniae, the leading cause of community-acquired pneumonia. At 16 weeks of age, CPEfat/fat mice develop severe obesity, hyperglycemia, elevated serum triglycerides and leptin, and increased blood neutrophil counts. There were no differences between lean WT and obese CPEfat/fat mice in survival or lung and spleen bacterial burdens following intratracheal infection with S. pneumoniae. Besides a modest increase in TNF-α levels and increased peripheral blood neutrophil counts in CPEfat/fat mice, there were not differences in lung or serum cytokines after infection. These results suggest that obesity, accompanied by hyperglycemia and modestly elevated triglycerides, at least in the case of CPEfat/fat mice, does not impair innate immunity against pneumococcal pneumonia.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "The pathologic response in sepsis is mediated through inflammatory cytokines [4], and comparable changes are seen in otherwise healthy patients with obesity [5-8]. Murine models of sepsis have demonstrated increased mortality in obese mice [9,10]. Recent investigations into the alterations in response to sepsis in these animal models have focused on hormonal mediators, including leptin and adiponectin [11-13]. "
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    ABSTRACT: Recent sepsis guidelines have focused on the early identification and risk stratification of patients on presentation. Obesity is associated with alterations in multiple inflammatory regulators similar to changes seen in sepsis, suggesting a potential interaction between the presence of obesity and the severity of illness in sepsis. We performed a retrospective chart review of patients admitted with a primary billing diagnosis of sepsis at a single United States university hospital from 2007 to 2010. Seven hundred and ninety-two charts were identified meeting inclusion criteria. Obesity was defined as a body mass index (BMI) >= 30 kg/m2. The data recorded included age, race, sex, vital signs, laboratory values, length of stay, comorbidities, weight, height, and survival to discharge. A modified APACHE II score was calculated to estimate disease severity. The primary outcome variable was inpatient mortality. Survivors had higher average BMI than nonsurvivors (27.6 vs. 26.3 kg/m2, p = 0.03) in unadjusted analysis. Severity of illness and comorbid conditions including cancer were similar across BMI categories. Increased incidence of diabetes mellitus type 2 was associated with increasing BMI (p < 0.01) and was associated with decreased mortality, with an odds ratio of 0.53 compared with nondiabetic patients. After adjusting for age, gender, race, severity of illness, length of stay, and comorbid conditions, the trend of decreased mortality for increased BMI was no longer statistically significant, however diabetes continued to be strongly protective (odds ratio 0.52, p = 0.03). This retrospective analysis suggests obesity may be protective against mortality in septic inpatients. The protective effect of obesity may be dependent on diabetes, possibly through an unidentified hormonal intermediary. Further prospective studies are necessary to elaborate the specific mechanism of this protective effect.
    Full-text · Article · Aug 2013 · BMC Infectious Diseases
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    • "Similarly, alveolar macrophages from ob/ob mice were impaired in their ability to phagocytose S. pneumoniae and PMNs displayed a reduction in killing. Again, administration of leptin restored proper effector functions in these cells 17. Alveolar macrophages express LepRb, and are capable of activating STAT3 following stimulation with leptin. "
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    ABSTRACT: Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that leptin deficiency affects both the innate and acquired immune systems. Here, we review recent studies that demonstrate the impact on immunity of a common non-synonomous polymorphism of the leptin receptor. In a Bangladesh cohort of children, the presence of two copies of the ancestral Q223 allele was significantly associated with resistance to amebiasis. Children and mice with at least one copy of the leptin receptor 223R mutation were more susceptible to amebic colitis. Leptin signaling in the intestinal epithelium and downstream STAT3 (signal transducer and activator of transcription 3) and SHP2 (Src homology phosphatase 2) signaling were required for protection in the murine model of amebic colitis. Murine models have also implicated leptin in protection from other infections, including Mycobacterium tuberculosis, Klebsiella pneumoniae, and Streptococcus pneumoniae. Thus, the role of leptin signaling in infectious disease and specifically leptin-mediated protection of the intestinal epithelium will be the focus of this review.
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