leptin and Sepsis

Infections and sepsis are common causes of morbidity and mortality, with an increasing incidence worldwide. Leptin is involved in the inflammatory process and may modulate the cytokine production, immune cell proliferation and endothelial function. There are conflicting results regarding alterations of leptin levels in infectious diseases and the outcome from sepsis.The aim of the current article is to provide an overview of the medical literature on the correlations between variations of leptin levels and infectious diseases and sepsis.. We performed an extensive literature search in PubMed and Google Scholar databases, using keywords to identify articles related to leptin in infectious diseases and sepsis. Searches were referenced using medical subject headings that included "leptin," "adipokines," "sepsis," "infectious diseases," "leptin deficiency," "leptin resistance" or "hyperleptinemia." The language of publication, journal, or country were not included as limitation criteria.Articles or abstracts containing adequate information, such as age, sex, anthropometric indices, clinical presentation, comorbidities, and management were included in the study, whereas articles with insufficient clinical and demographic data were excluded. We assessed the quality of the studies selected.The final review of all databases was conducted on June 18, 2020.. We find the results from the current review to be of great importance due to the possible therapeutic role of leptin analogs in states of leptin deficiency associated with infectious diseases or sepsis.In hyperleptinemia, a therapeutic plan for obtaining leptin neutralization also needs further investigations. This could lead to the reduction of proinflammatory responses.There is a need for further studies to demonstrate the specificity and sensitivity of leptin in the early diagnosis of sepsis and the need to measure serum leptin levels in routine evaluation of the critical patient.. The multiple effects of leptin are of growing interest, but further studies are needed to elucidate the role of leptin signalling in infectious diseases and sepsis. Because very few human studies are reported, we recommend the need for further research.Better understanding of the pathophysiology of sepsis and the implication of circulating total leptin in this process could help physicians in managing this life-threatening condition.

Topics: Communicable Diseases; Drug Discovery; Early Diagnosis; Humans; Leptin; Prognosis; Sepsis

Sepsis has become a global health problem with rising incidence and high mortality, creating a substantial social and economic burden. Early diagnosis and treatment can improve outcome, but reliable sepsis biomarkers are lacking. This review summarizes current evidence of the pathophysiological mechanisms linking adipose tissue to sepsis and presents experimental and clinical data on adipokines and sepsis along with important insights into the obesity paradox in sepsis survival.. Sepsis is characterized by significant alterations in circulating cytokines and adipokines, biologically active molecules produced by the adipose tissue, being implicated in metabolic and inflammatory processes. Although data are inconclusive regarding classic adipokines such as leptin and adiponectin, recent evidence have highlighted the striking elevation of resistin and visfatin in critical illness and sepsis as well as their association with sepsis severity and outcomes. Given that inflammatory and metabolic pathways are involved in sepsis, studying adipokines presents an attractive, innovative, and promising research field that may provide more powerful diagnostic and prognostic biomarkers as well as novel therapeutic targets, empowering the therapeutic armamentarium for sepsis management in order to improve survival.

Topics: Adipokines; Adiponectin; Adipose Tissue; Animals; Biomarkers; Cytokines; Humans; Hyperglycemia; Insulin Resistance; Leptin; Nicotinamide Phosphoribosyltransferase; Obesity; Resistin; Sepsis; Severity of Illness Index

Sepsis, which is defined as a systemic inflammatory response syndrome that occurs during infection, is associated with several clinical conditions and high mortality rates. As sepsis progresses immune paralysis can become severe, leaving an already vulnerable patient ill equipped to eradicate primary or secondary infections. At present the predominant treatments for sepsis have not demonstrated convincing efficacy of decreased mortality. During sepsis, it has been observed that leptin levels initially increase but subsequently decline. A body of evidence has demonstrated that central or systemic leptin can beneficially regulate immune function. In this report expression of leptin and its receptor, signaling, and function on leukocytes will be reviewed. Furthermore, the effects mediated by central and systemic leptin during sepsis will be reviewed. Altogether, the ability of leptin to beneficially enhance inflammation and the host response during sepsis supports its use as a therapeutic agent, particularly during the latter phases of the syndrome.

Topics: Animals; Cytokines; Immune Tolerance; Immunologic Factors; Inflammation Mediators; Leptin; Leukocytes; Receptors, Leptin; Sepsis; Signal Transduction

Leptin, 16 kDa protein and the product of the Ob gene was discovered six years ago and characterized as a fat cell hormone which maintains via specific receptors in the hypothalamus by a feedback mechanism the energy balance and body weight. Research conducted during the last three years detected further properties of this protein which include it, in addition to its basic role in mammalian metabolism, also among acute phase reactants. Leptin is as to its structure, pattern of the receptor and the postreceptor transduction mechanism close to the group of cytokines of interleukin 6, in particular the granulocytic colony stimulating factor. During infectious and non-infectious inflammatory reactions leptin synthesis is stimulated by a combination of inflammation promoting cytokines. The mechanism of induction is not known so far but the majority of investigations proves an indirect stimulating effect of the tumour necrosis factor and interleukin 1, depending on non-specified cytokines of the second stage. Investigations of cell lines and animal experiments provided evidence of some local and systemic effects of leptin which may play a physiological part in the acute phase reaction. Leptin mediates at least partly the anorectic effect of the tumour necrosis factor and interleukin 1 during inflammation. Synergically with bacterial antigens it activates macrophages, enhances their phagocytic capacity and stimulates secretion of pro- and anti-inflammatory factors from macrophages. Leptin stimulates neovascularization, it has a stimulating effect on precursors of white blood cells and potentiates the effect of erythropoietin on red blood cells. It is obviously an essential factor for T-lymphocyte proliferation and development. The authors discuss also the role of leptin in the modulation of the hypothalamo-pituito-adrenal stress axis. Leptin is a factor of the inflammatory mediator network, probably essential for an adequate course of the inflammatory defence reaction.

Topics: Acute-Phase Proteins; Acute-Phase Reaction; Animals; Cytokines; Humans; Leptin; Myocardial Infarction; Sepsis

The adipokine leptin regulates energy expenditure, vascular function, bone and cartilage growth as well as the immune system and systemic inflammatory response. Several activating effects towards T cells, monocytes, endothelium cells and cytokine production have been reported suggesting a protective role of leptin in the setting of an acute systemic inflammation. However, the pathophysiological role of leptin during severe sepsis is currently not elucidated in detail. This study aims to investigate leptin expression in cultured human adipocytes within an inflammatory model and in patients suffering from severe sepsis and evaluates treatment effects of drotrecogin alpha (activated) (DAA), the recombinant form of human activated protein C.. In an in-vitro inflammatory model of adipocyte cell-culture the effect of DAA on leptin mRNA expression was evaluated. Synthesis of mRNA was measured by quantitative polymerase chain reaction (qPCR). Additionally, supernatants of these adipocytes as well as serum levels of adiponectin were measured in blood of 104 severe septic patients by ELISA-method. 26 patients were treated with DAA (DAA+), 78 patients were not treated with DAA (DAA-).. Stimulation of human adipocytes with TNF alpha over 6 and 24 hours resulted in a significant decrease by 46% and 59% of leptin mRNA transcripts compared to un-stimulated controls (p < 0.05). Leptin levels of supernatants of adipocyte culture decreased by 25% and 23% (p < 0.05) after incubation with TNF alpha after 6 and 24 hours. Incubation with DAA at 50 ng/ml DAA and 5 μg/ml doubled mRNA expression significantly at 24 hours (p < 0.05) but not at 6 hours. From day 1 to day 3 of sepsis, leptin levels increased in DAA+ compared to DAA- patients (p<0.10).. Leptin appears to be involved in the pathogenesis of a systemic inflammatory response during sepsis. Administration of DAA significantly increased leptin expression. The specific mechanism or even benefit of DAA towards leptin needs further ongoing research.

Topics: Adipocytes; Adult; Aged; Aged, 80 and over; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Profiling; Humans; Inflammation; Leptin; Male; Middle Aged; Protein C; Real-Time Polymerase Chain Reaction; Recombinant Proteins; Sepsis; Serum; Transcription, Genetic; Treatment Outcome

Intensive care patients with organ failure often suffer an acute catabolic state. Leptin is a 16-kDa hormone which is produced by mature adipocytes and correlates with human energy expenditure. We investigated whether continuous venovenous haemofiltration, which may eliminate molecules up to 20-30 kDa, is capable of removing human leptin. Leptin measurements were made in the plasma of 15 patients with sepsis before continuous venovenous haemofiltration (T0) and during the procedure at 24 h (T1), 48 h (T2), and 72 h (T3), using samples taken before and after haemofiltration. In addition, measurements were made in the ultrafiltrate at T1-T3. The plasma leptin level at T0 was 17.6 ng mL-1. The concentration at T1 was 17.5 ng mL-1 pre-filter and 26.5 ng mL-1 post-filter (T2: 14.2/23.2 ng mL-1; T3: 12.4/16.3 ng mL-1). This concentration effect after haemofiltration was also seen with albumin. The values measured at T3 tended to be lower than those recorded at T1. The mean leptin levels in the ultrafiltrate were 0.15-0.18 ng mL-1. The range of leptin levels in the ultrafiltrate was thus only 0.5-3% of that measured in plasma. We conclude that human leptin is only minimally elimininated into the ultrafiltrate by continuous venovenous haemofiltration and that plasma leptin levels may decrease during sepsis.

Topics: Aged; Female; Hemofiltration; Humans; Intensive Care Units; Kinetics; Leptin; Male; Sepsis; Serum Albumin

Introduction: The dysregulated immune response in sepsis is highly variable, ranging from hyperinflammation to immunoparalysis. Obesity is associated with the release of inflammatory mediators from adipose tissue, known as adipocytokines, causing a chronic inflammatory state. Perhaps counterintuitively, obesity is also associated with lower mortality in sepsis patients. We investigated the association between obesity, circulating adipocytokine concentrations, immune dysregulation, and outcome in sepsis patients. Methods In this secondary analysis of a prospective study, plasma concentrations of the adipocytokines leptin, adiponectin, and resistin were assessed in 167 patients at diagnosis of sepsis due to pneumonia, bacteremia, or acute cholangitis. Adipocytokines were compared between patients with normal weight (body mass index [BMI], 18.5-24.9 kg/m 2 ; n = 67), overweight (BMI, 25.0-29.9 kg/m 2 ; n = 56), and obesity (BMI ≥30 kg/m 2 ; n = 42), as well as between immunological endotypes: hyperinflammation (n = 40), immunoparalysis (n = 62), and unclassified (n = 55). Results: Higher circulating concentrations of leptin were observed in patients with obesity compared with patients with normal weight ( P = 0.008) and overweight ( P = 0.02), whereas adiponectin and resistin plasma concentrations were not different ( P = 0.08 and P = 0.85, respectively). Resistin concentrations were associated with immunological endotypes, with the highest levels found in hyperinflammatory patients ( P < 0.001). Furthermore, resistin concentrations were predictive for 28-day mortality (adjusted odds ratio, 1.03 per 10 ng/mL; P = 0.04). These associations were not found for leptin and adiponectin. Conclusion: Obesity and BMI-related adipocytokines are not related to the development of a hyperactive or suppressed immune response as defined by ferritin and mHLA-DR expression in sepsis patients. Although resistin is related to the immune response and an increased risk of adverse clinical outcomes, these associations are similar in patients with normal weight, overweight, and obesity. This implies that the relationship between resistin and clinical outcome is likely driven by the inflammatory response and not by obesity itself. Taken together, although there exists a strong association between inflammation and sepsis mortality, our results do not point toward a role for obesity and BMI-related adipocytokines in immune dysregulation in sepsis patients.

Topics: Adipokines; Adiponectin; Humans; Inflammation; Leptin; Obesity; Overweight; Prospective Studies; Resistin; Sepsis

Introduction: Sepsis is a dysregulated host response to infection that can lead to life-threatening organ dysfunction. Clinical and animal studies consistently demonstrate that female subjects are less susceptible to the adverse effects of sepsis, demonstrating the importance of understanding how sex influences sepsis outcomes. The signal transducer and activator of transcription 3 (STAT3) pathway are a major signaling pathway that facilitates inflammation during sepsis. STAT3 is abundantly expressed in white adipose tissue; however, little is known about the contribution of white adipose tissue STAT3 activation during sepsis. We hypothesize that adipocyte STAT3 inhibition during severe sepsis will exaggerate the inflammatory response and impact organ injury, in a sex-dependent manner. Methods: We generated STAT3 flox/flox (wild-type [WT]) and adipocyte STAT3 knock out (A-STAT3 KO) mice using Cre-lox technology. Studies were done in 12- to 16-week-old male and female mice. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP). Control nonseptic mice did not undergo CLP (0 h CLP). Tissues were harvested 18 h after CLP. Body composition was determined by echo magnetic resonance imaging. Energy metabolism was determined by indirect calorimetry. White adipose tissue morphology was determined by hematoxylin and eosin staining, while STAT3 activation in the white adipose tissue was determined by western blot analysis and immunohistochemistry staining of STAT3 activation/phosphorylation at tyrosine 705. Plasma cytokines (TNF-α, IL-6, and leptin) were determined by luminex assay. Neutrophil infiltration of the lung and liver was assessed by myeloperoxidase activity assay. Histological signs of organ injury on lung and liver tissue were assessed by hematoxylin and eosin staining. Liver injury was further assessed by measuring plasma alanine and aspartate aminotransferase. In a separate cohort of mice, sepsis was induced by CLP and mice were monitored every 6-12 h over a 7-day period to assess survival rate. Results: We demonstrate that neither body composition nor energy metabolism is altered with adipocyte STAT3 inhibition in male or female mice, under nonseptic conditions. Sepsis was associated with reduced adipocyte size in female WT and A-STAT3 KO mice, suggesting that this event is STAT3 independent. Sepsis did not alter adipocyte size in male WT and A-STAT3 KO mice, suggesting that this event is also sex dependent. Although STAT3 phosphorylat

Topics: Adipocytes; Animals; Cytokines; Disease Models, Animal; Eosine Yellowish-(YS); Hematoxylin; Inflammation; Interleukin-6; Leptin; Lung Injury; Male; Mice; Mice, Inbred C57BL; Sepsis; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Muscle weakness is a frequently occurring complication of sepsis, associated with increased morbidity and mortality. Interestingly, obesity attenuates sepsis-induced muscle wasting and weakness. As the adipokine leptin is strongly elevated in obesity and has been shown to affect muscle homeostasis in non-septic conditions, we aimed to investigate whether leptin mediates the protective effect of obesity on sepsis-induced muscle weakness.. In a mouse model of sepsis, we investigated the effects of genetic leptin inactivation in obese mice (leptin-deficient obese mice vs. diet-induced obese mice) and of leptin supplementation in lean mice (n = 110). We assessed impact on survival, body weight and composition, markers of muscle wasting and weakness, inflammation, and lipid metabolism. In human lean and overweight/obese intensive care unit (ICU) patients, we assessed markers of protein catabolism (n = 1388) and serum leptin (n = 150).. Sepsis mortality was highest in leptin-deficient obese mice (53% vs. 23% in diet-induced obese mice and 37% in lean mice, P = 0.03). Irrespective of leptin, after 5 days of sepsis, lean mice lost double the amount of lean body mass than obese mice (P < 0.0005). Also, irrespective of leptin, obese mice maintained specific muscle force up to healthy levels (P = 0.3) whereas lean mice suffered from reduced specific muscle force (72% of healthy controls, P < 0.0002). As compared with lean septic mice, both obese septic groups had less muscle atrophy, liver amino acid catabolism, and inflammation with a 50% lower plasma TNFα increase (P < 0.005). Conversely, again mainly irrespective of leptin, obese mice lost double amount of fat mass than lean mice after 5 days of sepsis (P < 0.0001), showed signs of increased lipolysis and ketogenesis, and had higher plasma HDL and LDL lipoprotein concentrations (P ≤ 0.01 for all). Muscle fibre type composition was not altered during sepsis, but a higher atrophy sensitivity of type IIb fibres compared with IIa and IIx fibres was observed, independent of obesity or leptin. After 5 days of critical illness, serum leptin was higher (P < 0.0001) and the net waste of nitrogen (P = 0.006) and plasma urea-to-creatinine ratio (P < 0.0001) was lower in overweight/obese compared with lean ICU human patients.. Leptin did not mediate the protective effect of obesity against sepsis-induced muscle wasting and weakness in mice. Instead, obesity-independent of leptin-attenuated inflammation, protein catabolism, and dyslipidaemia, pathways that may play a role in the observed muscle protection.

Topics: Animals; Dyslipidemias; Humans; Leptin; Mice; Muscle Weakness; Obesity; Sepsis

Leptin, the prototype adipokine, exerts immunomodulatory actions being implicated in inflammatory responses during sepsis. Clinical evidence regarding its role in sepsis has been contradictory, while free leptin has not been studied. The aim of this study was to jointly investigate circulating total leptin, its soluble receptor (sOB-R), and free leptin, as well as their kinetics in critically ill patients with sepsis regarding their diagnostic and prognostic value.. In a prospective study, serum total leptin, sOB-R and free leptin index (FLI) were determined in 102 critically ill patients with sepsis within 48 hours from sepsis onset and one week after enrollment, and in 102 age and gender-matched healthy controls.. Upon enrolment, total leptin, sOB-R and FLI were significantly higher in septic patients compared to controls and they were positively correlated with sepsis severity scores, while they presented a significant decrease during the first week (P<0.001). The decrease in total leptin and sOB-R was significantly higher in patients with sepsis compared to septic shock and in survivors compared to non-survivors at 28 days (P<0.001). Higher serum total leptin was independently associated with survival at 28 days (enrollment: HR 0.86, P=0.03; one week after: HR 0.77, P<0.001). Higher kinetics of total leptin (but not FLI) was independently associated with survival after adjustment (HR: 0.48, P=0.001).. Higher circulating total leptin and its higher kinetics during the first week from sepsis onset independently predict 28-day survival in critically ill patients. Free leptin did not present any additional diagnostic and prognostic value in sepsis.

Topics: Critical Illness; Humans; Leptin; Prospective Studies; Receptors, Leptin; Sepsis

Ghrelin is a hormone mainly produced by cells of the gastric mucosa, which has been shown to possess anti-inflammatory and immunomodulatory properties. The objective of the study was to investigate ghrelin levels during sepsis, as well as in an experimental sepsis model.. All consecutive admissions to the ICU of a tertiary hospital in Athens, Greece were screened for eligibility during the study. Thirty four non-septic patients upon ICU admission who subsequently developed sepsis were enrolled. Clinical data and scores were recorded, and blood samples were obtained at baseline (upon ICU admission), and at sepsis development. Total and active ghrelin, leptin, and cytokines were measured. Moreover, lipopolysaccharide (LPS) was administered to mice in order to induce endotoxemia and at specified time points, blood and tissue samples were collected.. In patients, serum total and active ghrelin concentrations were significantly elevated in sepsis compared to baseline (553.8 ± 213.4 vs 193.5 ± 123.2, p < 0.001; 254.3 ± 70.6 vs 56.49 ± 16.3, p < 0.001). Active ghrelin levels at the sepsis stage were inversely correlated with SOFA score and length of stay in the ICU (p = 0.023 and p = 0.027 respectively). In the mouse endotoxemia model ghrelin levels were elevated following LPS treatment, and the same trend was observed for leptin, TNFα and IL-6. Ghrelin administration managed to reduce IL-6 levels in mouse serum and in BALF. Pulmonary expression of ghrelin and its receptor GHSR1a was found decreased in LPS-treated mice.. In a well-defined cohort of ICU patients, we have demonstrated that active and total ghrelin increase in sepsis. The same is true for the experimental sepsis model used in the study. The inverse correlation of active ghrelin levels with SOFA score and length of ICU stay among septic patients is indicative of a potential protective role of active ghrelin during the septic process.

Topics: Animals; Critical Illness; Cytokines; Endotoxemia; Enzyme-Linked Immunosorbent Assay; Female; Ghrelin; Humans; Intensive Care Units; Leptin; Lipopolysaccharides; Male; Mice, Inbred C57BL; Middle Aged; Sepsis

Leptin is thought to play an important role in the regulation of the immune system. In patients, leptin is inversely proportional to interleukin-6 (IL-6) levels. Thus, the objective of our study was to evaluate a dose-dependent therapeutic impact of leptin with possible IL-6-dependency on immune actions and outcome in a trauma/sepsis model.. Sixty-nine wild-type and 63 IL-6 mice were subdivided into three groups: trauma/sepsis group (first hit: femur fracture and hemorrhage; second hit: cecal ligation and puncture 2 days later), trauma group (first hit and laparotomy), sham group (laparotomy only). Each group received vehicle or leptin (2.5 μg/g (leptin1) or 5 μg/g (leptin2)) subcutaneously and was observed for 8 days after induction of the first hit. Mortality, humoral, and cellular immune markers were determined.. We revealed a dose-dependent anti-inflammatory effect of exogenous leptin in the sepsis groups and to some extent a pro-inflammatory effect in the sham groups. Leptin administration resulted in a decreased mortality in septic wild-type mice (trauma/sepsis vehicle group: 36.4%, trauma/sepsis leptin1 group: 25%, trauma/sepsis leptin2 group: 0%) and in an increased mortality in septic IL-6 mice (53.8%, 83.4%, 100%). All mice of the trauma groups and sham groups survived. In wild-type trauma/sepsis mice, exogenous leptin led to increased levels of CD4 and CD8 in the spleen, and a less pronounced type IV hypersensitivity (P ≤ 0.039). Furthermore, it decreased the levels of tumor necrosis factor-α and IL-6, not reaching statistical significance.. Due to the fact that leptin administration to traumatized and septic mice seems to have a positive effect on their outcome via IL-6 and does not negatively impact their medical condition if applied preventively, leptin might be a therapeutic agent for the prevention, or treatment of sepsis-related detrimental outcome after initial trauma.

Topics: Animals; Anti-Inflammatory Agents; Immunity, Cellular; Immunity, Humoral; Interleukin-6; Leptin; Mice; Mice, Inbred C57BL; Mice, Knockout; Sepsis; Wounds and Injuries

Topics: Humans; Inflammation; Leptin; Sepsis

How obesity affects the response to sepsis was not completely understood. It was hypothesized that obesity alters adipose and hepatic tissue inflammation through signal transducer and activator of transcription (STAT3) activation.. Male C57BL/6 mice at 6 weeks of age were randomized to a high-fat diet (60% kcal fat) or normal diet (16% kcal fat) for 6 to 7 weeks. Sepsis was then induced by cecal ligation and puncture, and animals were monitored for survival or sacrificed and tissue collected.. High-fat diet-fed mice gained more weight, had increased fat mass, and were glucose intolerant compared with normal diet-fed mice. Obesity increased hepatic neutrophil infiltration and injury after sepsis. Mice with obesity had higher plasma leptin levels compared with mice without obesity. Adipose tissue expression of adiponectin receptor 2, tumor necrosis factor-α, and peroxisome proliferator activated receptor gamma was altered during sepsis and affected by obesity, but the greatest change in adipose tissue expression was in leptin. Septic mice with obesity had lower plasma interleukin-17a, interleukin-23, and tumor necrosis factor-α levels and increased hepatic STAT3 and activator protein-1 activation compared with septic mice without obesity. Ultimately, mice with obesity had a lower probability of survival following sepsis.. Mice with obesity are more susceptible to sepsis and have higher mortality, in part, through activation of the STAT3 signaling pathway and through activator protein-1 activation.

Topics: Adipose Tissue; Animals; Cecum; Diet, High-Fat; Hepatitis; Inflammation; Interleukin-17; Interleukin-23; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Sepsis; Signal Transduction; STAT3 Transcription Factor; Transcription Factor AP-1; Tumor Necrosis Factor-alpha

It is well established that obesity-related hormones can have modulatory effects associated with the immune response. Ghrelin, a hormone mainly derived from endocrine cells of the gastric mucosa, regulates appetite, energy expenditure and body weight counteracting leptin, a hormone mainly derived from adipocytes. Additionally, receptors of both have been detected on immune cells and demonstrated an immune regulatory function during sepsis.. In the present study, the effect of peripheral ghrelin administration on early immune response and survival was investigated with lean mice and mice with diet-induced obesity using cecal ligation and puncture to induce sepsis.. In the obese group, we found that ghrelin treatment improved survival, ameliorated hypothermia, and increased hyperleptinemia as compared to the lean controls. We also observed that ghrelin treatment divergently regulated serum IL-1ß and TNF-α concentrations in both lean and obese septic mice. Ghrelin treatment initially decreased but later resulted in increased bacteriaemia in lean mice while having no impact upon obese mice. Similarly, ghrelin treatment increased early neutrophil oxidative burst while causing a decrease 48 hours after sepsis inducement.. In conclusion, as the immune response to sepsis temporally changes, ghrelin treatment differentially mediates this response. Specifically, we observed that ghrelin conferred protective effects during the early phase of sepsis, but during the later phase deteriorated immune response and outcome. These adverse effects were more pronounced upon lean mice as compared to obese mice.

Topics: Animals; Disease Models, Animal; Ghrelin; Interleukin-1beta; Leptin; Mice; Mice, Obese; Neutrophils; Obesity; Sepsis; Survival Analysis; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Obesity is a risk factor for sepsis morbidity and mortality, whereas the hypothalamic-pituitary-adrenal (HPA) axis plays a protective role in the body's defence against sepsis. Sepsis induces a profound systemic immune response and cytokines serve as excellent markers for sepsis as they act as mediators of the immune response. Evidence suggests that the adipokine leptin may play a pathogenic role in sepsis. Mouse endotoxaemic models present with elevated leptin levels and exogenously added leptin increased mortality whereas human septic patients have elevated circulating levels of the soluble leptin receptor (Ob-Re). Evidence suggests that leptin can inhibit the regulation of the HPA axis. Thus, leptin may suppress the HPA axis, impairing its protective role in sepsis. We hypothesised that leptin would attenuate the HPA axis response to sepsis. We investigated the direct effects of an i.p. injection of 2 mg/kg leptin on the HPA axis response to intraperitoneally injected 25 μg/kg lipopolysaccharide (LPS) in the male Wistar rat. We found that LPS potently activated the HPA axis, as shown by significantly increased plasma stress hormones, ACTH and corticosterone, and increased plasma interleukin 1β (IL1β) levels, 2 h after administration. Pre-treatment with leptin, 2 h before LPS administration, did not influence the HPA axis response to LPS. In turn, LPS did not affect plasma leptin levels. Our findings suggest that leptin does not influence HPA function or IL1β secretion in a rat model of LPS-induced sepsis, and thus that leptin is unlikely to be involved in the acute-phase endocrine response to bacterial infection in rats.

Topics: Adrenocorticotropic Hormone; Animals; Disease Models, Animal; Humans; Hypothalamo-Hypophyseal System; Leptin; Lipopolysaccharides; Male; Pituitary-Adrenal System; Rats; Rats, Wistar; Sepsis

Obesity is a growing health problem and associated with immune dysfunction. Sepsis is defined as systemic inflammatory response syndrome that occurs during infection. Excessive inflammation combined with immune dysfunction can lead to multiorgan damage and death.. The authors investigated the influence of a class 1 obesity (body mass index between 30 and 34.9) on immune function and outcome in sepsis and the role of leptin on the immune response. The authors used a long-term high-fat-diet feeding model (12 weeks) on C57Bl/6 mice (n = 100) and controls on standard diet (n = 140) followed by a polymicrobial sepsis induced by cecal ligation and puncture.. The authors show that class 1 obesity is connected to significant higher serum leptin levels (data are mean ± SEM) (5.7 ± 1.2 vs. 2.7 ± 0.2 ng/ml; n = 5; P = 0.033) and improved innate immune response followed by significant better survival rate in sepsis (71.4%, n = 10 vs. 10%, n = 14; P < 0.0001). Additional sepsis-induced increases in leptin levels stabilize body temperature and are associated with a controlled immune response in a time-dependent and protective manner. Furthermore, leptin treatment of normal-weight septic mice with relative hypoleptinemia (n = 35) also significantly stabilizes body temperature, improves cellular immune response, and reduces proinflammatory cytokine response resulting in improved survival (30%; n = 10).. Relative hyperleptinemia of class 1 obesity or induced by treatment is protective in sepsis. Leptin seems to play a regulatory role in the immune system in sepsis, and treatment of relative hypoleptinemia could offer a new way of an individual sepsis therapy.

Topics: Animals; Body Temperature; Bronchoalveolar Lavage Fluid; Cecum; Colony Count, Microbial; Cytokines; Dietary Fats; Eating; Flow Cytometry; Immunity, Cellular; Inflammation; Injections, Intraperitoneal; Leptin; Leukocyte Count; Ligation; Mice; Mice, Inbred C57BL; Neutrophils; Obesity; Respiratory Burst; Sepsis; Survival

Obesity is associated with elevated levels of IL-6. High IL-6 is prognostic of mortality in sepsis, while controversial data link obesity to sepsis outcome. We used Lean and diet-induced obese (DIO) WT and IL-6 KO mice to investigate the interaction between obesity and IL-6 in endotoxemia. Circulating levels of IL-6 were significantly higher in WT DIO versus WT Lean mice receiving LPS (2.5 μg/mouse, ip). Obesity lead to greater weight loss in response to LPS, with IL-6 deficiency being partially protective. Plasma TNFα, IFNγ, Galectin-3 and leptin were significantly elevated in response to LPS and were each differentially affected by obesity and/or IL-6 deficiency. Plasma Galectin-1 and adiponectin were significantly suppressed by LPS, with obesity and IL-6 deficiency modulating the response. However, LPS comparably increased IL-10 levels in each group. Leukopenia with relative neutrophilia and thrombocytopenia developed in each group after injection of LPS, with obesity and genotype affecting the kinetics, but not the magnitude, of the response. Hepatic induction of the acute-phase protein SAA by LPS was not affected by obesity or IL-6 deficiency, although baseline levels were highest in WT DIO mice. Injection of LPS significantly increased hepatic mRNA expression of PAI-1 in Lean WT and Lean KO mice, while it suppressed the high baseline levels observed in the liver of DIO WT and DIO KO mice. Thus, both IL-6 and obesity modulate the response to endotoxemia, suggesting a complex interaction that needs to be considered when evaluating the effect of obesity on the outcome of septic patients.

Topics: Animals; Endotoxemia; Galectin 3; Interferon-gamma; Interleukin-10; Interleukin-6; Leptin; Leukopenia; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Neutrophils; Obesity; RNA; Sepsis; Serpin E2; Thrombocytopenia; Tumor Necrosis Factor-alpha

The purpose of this study was to examine the effect of short-term high fat feeding on the inflammatory response in polymicrobial sepsis. Male C57BL/6 mice at 6 weeks of age were randomized to a high-fat diet (HFD) (60% kcal fat) or control diet (CD) (16% kcal fat) for 3 weeks. After 3 weeks of feeding, sepsis was induced by cecal ligation and puncture (CLP) and animals were monitored for survival. In a separate experiment, after 3 weeks of feeding mice underwent CLP and were sacrificed at various time points thereafter. Tissue was collected for biochemical studies. Mice fed a HFD gained more weight and had a greater fat mass compared to CD-fed mice. Mice on a HFD had a lower probability of survival and more severe lung injury compared with CD-fed mice following sepsis. Myeloperoxidase (MPO) activity, an indicator of neutrophil infiltration, was increased in the lung and liver after CLP in HFD-fed mice compared with CD (P < 0.05). The plasma cytokines tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were increased in both groups after CLP, however, TNF-α and IL-6 levels were lower in HFD mice at 3 h after CLP compared with CD and consistent with lung, but not liver, messenger RNA (mRNA) expression. Leptin levels were higher in HFD-fed mice at 18 h after sepsis compared to baseline levels (P < 0.05). Polymicrobial sepsis increased hepatic nuclear factor-κB (NF-κB) activation in HFD-fed mice after CLP vs. CD-fed mice. Short duration high fat feeding increases mortality and organ injury following polymicrobial sepsis. These effects correspond to changes in NF-κB.

Topics: Animals; Cecum; Diet, High-Fat; Interleukin-6; Leptin; Ligation; Liver; Lung; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Sepsis; Time Factors; Tumor Necrosis Factor-alpha

The acute phase response (APR) produces marked alterations in lipid and carbohydrate metabolism including decreasing plasma ketone levels. Fibroblast growth factor 21 (FGF21) is a recently discovered hormone that regulates lipid and glucose metabolism and stimulates ketogenesis. Here we demonstrate that lipopolysaccharide (LPS), zymosan, and turpentine, which induce the APR, increase serum FGF21 levels 2-fold. Although LPS, zymosan, and turpentine decrease the hepatic expression of FGF21, they increase FGF21 expression in adipose tissue and muscle, suggesting that extrahepatic tissues account for the increase in serum FGF21. After LPS administration, the characteristic decrease in plasma ketone levels is accentuated in FGF21-/- mice, but this is not due to differences in expression of carnitine palmitoyltransferase 1α or hydroxymethyglutaryl-CoA synthase 2 in liver, because LPS induces similar decreases in the expression of these genes in FGF21-/- and control mice. However, in FGF21-/- mice, the ability of LPS to increase plasma free fatty acid levels is blunted. This failure to increase plasma free fatty acid could contribute to the accentuated decrease in plasma ketone levels because the transport of fatty acids from adipose tissue to liver provides the substrate for ketogenesis. Treatment with exogenous FGF21 reduced the number of animals that die and the rapidity of death after LPS administration in leptin-deficient ob/ob mice and to a lesser extent in control mice. FGF21 also protected from the toxic effects of cecal ligation and puncture-induced sepsis. Thus, FGF21 is a positive APR protein that protects animals from the toxic effects of LPS and sepsis.

Topics: 3T3-L1 Cells; Acute-Phase Reaction; Animals; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fatty Acids, Nonesterified; Female; Fibroblast Growth Factors; Kaplan-Meier Estimate; Ketones; Leptin; Lipopolysaccharides; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha; Reverse Transcriptase Polymerase Chain Reaction; Sepsis

Severe infection and sepsis are common causes of morbidity and mortality. Early diagnosis in critically ill patients is important to reduce these complications. The present study was conducted to determine the role of serum leptin at early diagnosis and differentiation between patients with manifestations of systemic inflammatory response syndrome (SIRS) and those with sepsis in patients suffering from a broad range of diseases in the intensive care unit (ICU) and its correlation with other biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).. One hundred and six adult ICU patients were observed. CRP, leptin, IL-6 and TNF-alpha were compared among the following groups: sepsis group (n = 40), SIRS group (n = 34) and non-SIRS group (n = 32). Patients were classified into these groups at the time of blood analysis for these biomarkers.. Non-significant differences were observed among patients in different groups regarding biomarkers on the day of ICU admission. On the second day of ICU admission, significant elevation of leptin, IL-6 and TNF-alpha occurred in the SIRS and sepsis groups. Delayed elevation of CRP started on the fourth day of ICU admission in patients with sepsis. At the end of the first week, only CRP level was elevated in septic patients.. Serum leptin correlates well with serum level of IL-6 and TNF-alpha. Leptin helps to differentiate SIRS from non-SIRS patients. CRP is a classic marker of sepsis but is of late onset.

Topics: Adult; Biomarkers; C-Reactive Protein; Critical Illness; Diagnosis, Differential; Early Diagnosis; Egypt; Female; Humans; Intensive Care Units; Interleukin-6; Leptin; Male; Middle Aged; Monitoring, Physiologic; Observation; Predictive Value of Tests; Prospective Studies; Sepsis; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

The value of monitoring serum leptin in critically ill patients is important for early diagnosis and differentiation between sepsis and non-infectious systemic inflammatory response syndrome (SIRS). The early diagnosis of sepsis, the identification of its origin, and an adequate therapeutic management are crucial to overcome sepsis-associated mortality. Cytokine levels are an obvious choice as sepsis markers, since cytokines are key mediators of the inflammatory response to sepsis. Leptin, a hormone mainly generated by adipocytes, acts centrally in the hypothalamus to regulate body weight and energy expenditure. There is, however, strong evidence that leptin is also involved in cell-mediated immunity and cytokine crosstalk. The finding that a serum leptin threshold of 38 microg/l can distinguish between sepsis and non-infectious SIRS (sensitivity 91.2%, specificity 85%) is the major finding in the article by Yousef and colleagues (in this issue). Much remains to be learned about the precise mechanisms by which leptin signaling participates in sepsis and non-infectious SIRS. This knowledge will potentially contribute to new therapeutic approaches.

Topics: Biomarkers; Critical Illness; Humans; Leptin; Sepsis

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 cytokine leptin was implicated to link inflammation and metabolic alterations. We investigated the potential role of leptin components in critically ill patients, because systemic inflammation, insulin resistance, and hyperglycemia are common features of critical illness. Upon admission to Medical Intensive Care Unit (ICU), free leptin and soluble leptin-receptor serum concentrations were determined in 137 critically ill patients (95 with sepsis, 42 without sepsis) and 26 healthy controls. Serum leptin or leptin-receptor did not differ between patients or controls and were independent of sepsis. However, serum leptin was closely associated with obesity and diabetes and clearly correlated with markers of metabolism and liver function. Leptin-receptor was an unfavourable prognostic indicator, associated with mortality during three years follow-up. Our study indicates a functional role of leptin in the pathogenesis of severe illness and emphasizes the impact of complex metabolic alterations on the clinical outcome of critically ill patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Critical Illness; Diabetes Mellitus; Diagnosis, Differential; Female; Glucose; Humans; Inflammation; Intensive Care Units; Kaplan-Meier Estimate; Leptin; Lipid Metabolism; Male; Middle Aged; Obesity; Prognosis; Receptors, Leptin; Sepsis; Young Adult

Although clinical obesity is associated with increases in the morbidity and mortality of sepsis, little is known about the mechanisms that underlie the influence of obesity on sepsis. The objective of this study was to determine (a) whether obesity is associated with exaggerated inflammatory and thrombogenic responses in the intestinal microvasculature of septic mice and (b) whether these microvascular alterations are related to changes in the serum levels of cytokines that are produced by adipose tissue. Intravital microscopy was used to quantify leukocyte and platelet adhesion in intestinal postcapillary venules of lean wild-type (WT) mice, and two murine models of obesity, that is, ob/ob and db/db mice. Sepsis was induced by cecal ligation and perforation (CLP). Serum cytokine levels were measured using a cytometric bead assay, whereas adipokines were quantified using enzyme-linked immunosorbent assay. Cecal ligation and perforation elicited significant increases in the adhesion of leukocytes and platelets in venules of lean WT mice. These CLP-induced adhesive interactions were much more pronounced in the microvasculature of both ob/ob and db/db mice. Cecal ligation and perforation was associated with significant increases in serum cytokines in both WT and ob/ob mice, but such changes were not detected in db/db mice. However, db/db (but not WT or ob/ob) mice did exhibit significant increases in serum leptin and adiponectin levels after CLP. Sepsis promotes more intense inflammatory and thrombogenic responses in the gut microcirculation of obese mice than in their lean counterparts. The obesity-enhanced microvascular dysfunction in septic mice shows no consistent correlation with serum cytokines or adipokines.

Topics: Adiponectin; Animals; Blood Platelets; Capillaries; Cell Adhesion; Cytokines; Humans; Inflammation; Intestinal Mucosa; Intestines; Leptin; Mice; Mice, Obese; Microcirculation; Obesity; Platelet Adhesiveness; Sepsis; Venules

Heart-type fatty acid-binding protein (H-FABP) is widely distributed and has been used to diagnose certain diseases. However, its alteration during infection-evoked organ dysfunction, and the potential association between leptin and it in injury or infection has not been investigated. In the current study, serum H-FABP, leptin, C-reactive protein and interleukin-1beta in the patients with pulmonary infection-induced multiple organ dysfunction were detected. Moreover, a mouse model of sepsis was established, and serum alanine transaminase, uric acid, tissue H-FABP, myeloperoxidase, superoxide dismutase activity and histological alterations in lung and intestine were investigated. Serum H-FABP and leptin increased simultaneously and significantly in the patients, and leptin alleviated pulmonary and intestinal injuries by restraining tissue H-FABP secretions in the mouse model of sepsis. Other investigated variables showed different but independent alterations. In conclusion, H-FABP represents a useful diagnostic marker for organ dysfunction, and its association with leptin will be a novel target for emergency aid.

Topics: Adult; Alanine Transaminase; Animals; Biomarkers; C-Reactive Protein; Fatty Acid Binding Protein 3; Fatty Acid-Binding Proteins; Female; Humans; Interleukin-1beta; Leptin; Male; Mice; Middle Aged; Multiple Organ Failure; Peroxidase; Rabbits; Radioimmunoassay; Reproducibility of Results; Sepsis; Superoxide Dismutase; Uric Acid

This study was aimed to investigate the prognostic value of tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), leptin and C-reactive protein (CRP) levels in newborn sepsis. A total of 57 newborns with nosocomial sepsis and 30 healthy newborns were included to the study. Serum TNF-alpha, IL-10, leptin (Biosource, Belgium) and CRP (Dade Behring, Germany) levels were investigated by ELISA methodology before the initiation of the therapy (day 0) and on the third and fifth days of therapy. Initial leptin levels were found to be high in the control group (p = 0.00) and CRP levels were found to be high in the patient group (p = 0.00). No significant difference was detected for IL-10 and TNF-alpha levels (p > 0.05). CRP levels were significantly higher in the patient group than the controls on the third day of the therapy (p = 0.001), however, no significant difference was detected for the other parameters (p > 0.05). On the fifth day of the therapy CRP (p = 0.023) and leptin (p = 0.00) levels were significantly high in the patient group and TNF-alpha in the control group (p = 0.00) while no significant difference was observed for IL-10 levels (p > 0.05). Mortality rate was 24.5%. When the mean TNF-alpha, IL-10, leptin and CRP levels on the 0th, 3rd and 5th days were analysed for alive (n = 43) and dead (n = 14) newborns with sepsis, it was observed that TNF-alpha, IL-10 and CRP levels were related with poor prognosis (p < 0.05). The ROC analysis performed for the determination of the prognostic performance of TNF-alpha and IL-10 revealed that these parameters had predictive value about mortality when their levels were above certain cut-off values (on the 5th day of therapy for IL-10 > 1.8 ng/ml and for TNF-alpha > 21.1 ng/ml). It can be concluded that besides routine laboratory parameters, serum TNF-alpha and IL-10 levels at the initiation of therapy and afterwards may help to predict prognosis and guide treatment in newborns with sepsis.

Topics: C-Reactive Protein; Case-Control Studies; Cross Infection; Enzyme-Linked Immunosorbent Assay; Humans; Infant, Newborn; Interleukin-10; Leptin; Predictive Value of Tests; Prognosis; ROC Curve; Sepsis; Tumor Necrosis Factor-alpha

To explore the distribution of leptin expression and the effect of sepsis on leptin protein and mRNA levels.. Vital organ samples including hypothalamus, lung, liver, spleen, stomach, duodenum, kidney, epididymal fat pad and testis of normal rats were collected. The mRNA expressions of leptin in those samples were determined by RT-PCR. The sepsis rat model induce by cecal ligation and perforation (CLP) was established, setting groups of sham-operation, CLP model, CLP + intralipid injection, CLP + estradiol injection and CLP + insulin injection, as the latter three groups were set to intervene energy metabolism and neuroendocrine function. Radioimmunoassay was applied to measure serum leptin concentrations in each group at 12 h after injury, while RT-PCR was also used to detect Leptin mRNA expressions in hypothalamus, fat and lung after injury.. Leptin mRNA expressions were confirmed in all the above nine vital organs, with the highest in kidney but the lowest in testis. The serum leptin level showed no significant difference between sham operation group and other four groups. Compared with sham operation group, the Leptin mRNA level in CLP group decreased significantly in hypothalamus, fat and lung, while that in the other three groups showed different changes. The effect of intralipid on Leptin mRNA expression was found to be a dual-direction pattern, with central stimulation but peripheral inhibition.. Leptin is widely expressed in multiple vital organs, and it may be a protective factor to promote recovery of sepsis-induced internal disorders.

Topics: Animals; Appendix; Gene Expression Profiling; Intestinal Perforation; Leptin; Ligation; Male; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sepsis

To detect the effect of sepsis on fatty acid binding proteins (FABP) levels and corresponding enzymes in lung and intestine of mice, and to explore the role for FABP in acute inflammation.. A sepsis model of mice made with cecum deligation and perforation was established, and a radioimmunoassay for FABP and 96-well spectrophotometry assays for myeloperoxidase (MPO) and superoxide dismutase (SOD) which were related with clearance of free radicals,were used to detect their levels in lung and intestine homogenized fluids. Hematoxylin-eosin stain was used simultaneously to check the histopathologic chanes of both tissues.. Compared with sham group (108.11 +/- 94.03 and 67.22 +/- 19.47 ng/ml) 6 h and 12 h after sepsis, FABP levels in lung and intestine were significantly higher (204.98 +/- 70.72 and 154.29 +/- 60.14 ng/ml), respectively. Twelve hours after leptin (0.1 mg/kg i p) and indomethacin (2 mg/kg i p) injection, lung FABP level decreased and was lower than septic group (P < 0.05). Moreover, 12 h after sepsis intestinal FABP increased, but it decreased after leptin injection (419.80 +/- 80.06 vs 191.09 +/- 96.75 ng/ml), while indomethacin injection had no such effect. MPO and SOD activities in lung and intestine changed accordingly with time after sepsis, the effect of leptin and indomethacin injections on it had no significant correlation with FABP changes.. Leptin can protect vital organ functions such as lung and intestine after sepsis, as FABP levels, the cellular injury marker, were significantly lower than groups without injection. And this effect might have no correlation with the clearance factors of oxygenic free radicals such as MPO and SOD.

Topics: Animals; Fatty Acid-Binding Proteins; Intestinal Mucosa; Leptin; Lung; Male; Mice; Mice, Inbred Strains; Peroxidase; Sepsis; Superoxide Dismutase

In this research, the role of leptin on sepsis-induced organ dysfunction was evaluated. Making use of a mice sepsis model, changes of alanine transaminase and uric acid in serum, myeloperoxidase activity, leptin levels and histological alterations in heart, lung, liver and kidney were determined. Results showed that sepsis induced significantly higher levels of serum alanine transaminase and uric acid, decreased tissue myeloperoxidase activity and leptin levels, and triggered distinct histological alterations. However, leptin and indomethacin injections reversed those impairments at 6h and/or 12h after injury. These data reveal a protective role of both leptin and indomethacin on vital organ functions after sepsis by recovering tissue myeloperoxidase activity.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Indomethacin; Kidney; Leptin; Liver; Lung; Mice; Mice, Inbred C57BL; Models, Biological; Neuroimmunomodulation; Peroxidase; Sepsis; Uric Acid

To detect the effect of sepsis on renal function and corresponding enzymes in mice, and to explore the role of leptin in acute inflammation.. Sepsis was reproduced by cecum ligation and puncture in mice. Serum uric acid (UA) and four enzymes related with synthesis of free radicals in kidney homogenized fluids, myeloperoxidase (MPO), glutathione-S-transferase (GST), xanthine oxidase (XOD) and superoxide dismutase (SOD) were determined with spectrophotometry, and leptin level in kidney was detected by radioimmunoassay. Histopathologic changes in kidney were observed with hematoxylin-eosin staining.. Twelve hours after leptin (0.08 mg/kg, i.p.) and indomethacin (8 mg/kg, i.p.) injection, serum UA was significantly decreased [(295.79+/-80.86) micromol/L and (281.78+/-46.35) micromol/L, respectively, vs. sepsis group (474.03+/-75.22) micromol/L]. At the same time, renal leptin levels in leptin injection group [(196.00+/-134.30) microg/g] 12 hours after sepsis and in indomethacin injection group [(169.30+/-132.00) microg/g] 6 hours after sepsis were also significantly higher than sepsis group [(61.65+/-27.29) microg/g]. Six and 12 hours after leptin and indomethacin injection, renal MPO, GST, XOD and SOD activities were affected to certain extent, as the results were not completely inhibited or enhanced. Nevertheless, leptin and indomethacin could promote scavenge and deactivation of free radicals.. Low dose leptin can ameliorate sepsis-induced renal injury, which may be related with scavenge and deactivation of free radicals in renal cells, and this mechanism is similar with that of indomethacin.

Topics: Animals; Disease Models, Animal; Kidney; Leptin; Male; Mice; Peroxidase; Random Allocation; Sepsis; Superoxide Dismutase; Uric Acid

Mortality due to meningococcal sepsis continues to be extremely high. Patients with a poor prognosis require aggressive therapy and should be identified early.. To investigate the clinical and biological factors associated with poor outcome.. Seventy-one children aged 2 months to 13 years with meningococcal sepsis were studied. Inclusion criteria were meningococcus isolation in cultures or characteristic clinical features with purpuric exanthema.. A correlational descriptive study was performed. In all patients we evaluated the Pediatric Risk of Mortality (PRISM), the Glasgow Scale for Meningococcal Sepsis (GSMS), polymorphonuclear (PMN) count and prolactin (PRL), leptin (LPT) and C-reactive protein (CRP) levels.. Fourteen children (19.7 %) died. Death was associated with multiple organ dysfunction syndrome (MODS) (p = 0.0001), high GSMS and PRISM scores (p = 0.0001) and to a lesser extent with shock (p = 0.01). In patients who died, the determinations showing greatest alteration at admission were PRL levels (p = 0.0009) and PMN count (p = 0.0005). CRP levels were not associated with differences in mortality but were high in patients with shock (p = 0.008). Children with high body weight percentiles were at greater risk of death and showed higher levels of PRL, PCT (p = 0.006) and LPT (p = 0.006), without differences in GSMS or PRISM scores. Age did not influence mortality or PRL levels but did influence GMSM and PRISM scores and PMN and CRP levels. These differences disappeared after the age of 2-3 years. In patients with MODS or shock, the only differences found were reduced PMN count (p = 0.0001) and elevated PRL levels (p = 0.0001).. In meningococcal sepsis, death is more frequent in children with high body weight percentiles. Moreover, these children present elevated PRL and LPT levels, although whether these variables act independently remains to be elucidated.

Topics: Adolescent; Anti-Bacterial Agents; C-Reactive Protein; Calcitonin; Child; Child, Preschool; Female; Humans; Infant; Leptin; Male; Meningococcal Infections; Prognosis; Risk Factors; Sensitivity and Specificity; Sepsis; Treatment Outcome

The principal aim of this study was to evaluate serum leptin concentrations and to analyze the interaction between serum leptin levels and C-reactive protein (CRP) levels, hematological parameters before and after antimicrobial therapy in neonates with bacterial septicemia. We studied 16 neonates with bacterial septicemia and 15 controls. Blood samples in neonates with septicemia were collected just before antimicrobial therapy and 2 weeks after treatment. The mean concentration of serum leptin, CRP levels, and immature/total neutrophil (IT) ratio in newborns with septicemia were significantly higher than those of controls at the start. Two weeks after treatment, serum leptin levels in newborns with septicemia had decreased and were similar to those of controls. Although there were positive correlations between serum leptin levels and serum CRP levels and IT ratio in the septicemic group at the start, there were no correlations between serum leptin levels and other hematological parameters. These results suggest that leptin is not only an adipostatic hormone but also a stress-related hormone.

Topics: Bacterial Infections; C-Reactive Protein; Humans; Infant, Newborn; Leptin; Leukocyte Count; Neutrophils; Sepsis; Stress, Physiological

Circulating leptin concentrations are raised in animal models of inflammation and sepsis and leptin production is also increased in rodents by administration of endotoxin or cytokines. The purpose of this study was to investigate the effect of sepsis on serum leptin concentration and whether circulating leptin was related to tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release in newborn infants. Plasma leptin, TNF-alpha and IL-6 were measured in 20 neonates with culture-proven sepsis as soon as sepsis was diagnosed and after recovery and in 15 healthy control infants. There was no significant difference in plasma leptin levels between septic and control infants (p > 0.05); there was also no difference in plasma leptin levels in septic neonates before and after therapy (p > 0.05). No relationship between leptin and TNF-alpha (r = 0.16, p > 0.05) or IL-6 (r = 0.12, p > 0.05) was identified. These findings suggest that a major role of leptin in acute neonatal sepsis appears unlikely.

Topics: Anti-Bacterial Agents; Body Mass Index; Candida albicans; Candidiasis; Escherichia coli Infections; Female; Humans; Infant, Newborn; Interleukin-6; Klebsiella Infections; Leptin; Male; Sepsis; Staphylococcal Infections; Tumor Necrosis Factor-alpha

The response to injury is dependent on several factors, including the type and extent of the injury, genetics, and the environment. In the present study, the genetic contribution to sepsis was evaluated in a mouse model. Sepsis was induced in two inbred mouse strains, C57BL/6J (B6) and A/J, by cecal ligation and single puncture (CLP). Frequency of mortality was significantly higher in B6 than A/J mice from 36 to 132 h after CLP. Plasma TNF-alpha, IL-1beta, and IL-6 levels were similar in both strains after CLP. IL-10 plasma levels were significantly higher in B6 mice as opposed to A/J mice after 24 h of CLP. Similarly, hepatic myeloperoxidase activity, an index of polymorphonuclear leukocytes, was elevated in B6 mice as compared with A/J mice after 24 h of CLP. On the contrary, metallothionein mRNA levels were higher in A/J mice compared with B6 mice. Finally, leptin levels were also higher in A/J than B6 mice within 19 h of CLP. This study demonstrates a genetic contribution in the response to sepsis.

Topics: Animals; Disease Models, Animal; Fibrinogen; Interleukin-1; Interleukin-10; Interleukin-6; Leptin; Liver; Male; Metallothionein; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Peroxidase; Sepsis; Species Specificity; Survival Rate; Tumor Necrosis Factor-alpha

Leptin is a hormone and acute phase reactant with multiple effects during both rest and inflammatory period. Effects of leptin in acute phase response cover a modulation of hypothalamo-pituitoadrenal (HPA) axis, too. In our study we evaluate the dynamics of leptin and glucocorticoid acute changes in model situations of infectious and non-infectious inflammatory reaction.. This study was realized on a group of patients 1--after operation of carcinoma coli (16 persons), 2--after laparoscopic non-adjustable gastric banding (13 persons), and patients 3--with development of postoperative intraabdominal sepsis (22 persons). Plasma levels of leptin, ACTH, cortisol, TNF-alpha, IL-6, C reactive protein (CRP), and alpha1-antitrypsin (AAT) were measured from -7 to +3 day related to surgery or 2nd day after a day when signs of sepsis were occurred.. All tested parameters responded to surgical trauma with elevation 12 h after operation except leptin that elevated +24 h after surgery. Maximal levels of measured parameters were found 12 h after surgery (for cortisol), 24 h after surgery (for leptin, TNF-alpha, IL-6), or 36 h after operation (for CRP and AAT). Maximal levels of cortisol after a resection of coli or maximal levels of leptin after laparoscopic gastric banding fall to septic range. Other parameters in uncomplicated postoperative period significantly differed from septic levels on p < 0.01. There wasn't found statistically significant correlation between leptin and cortisol or between leptin and ACTH in all groups.. The elevation of leptin in postoperative period and during sepsis reflects a different regulation of this protein in rest period and during systemic inflammatory response. The inhibitory effect of leptin to HPA axis during stress response was documented in vitro, however, its physiological importance is not clear, yet. Our study didn't prove a statistically significant relation between plasma cortisol and leptin. The different dynamics of leptin and cortisol after surgical trauma shows that both factors have own specific regulation.

Topics: Acute-Phase Reaction; Adrenocorticotropic Hormone; Adult; Aged; alpha 1-Antitrypsin; C-Reactive Protein; Colorectal Neoplasms; Gastroplasty; Humans; Hydrocortisone; Leptin; Male; Middle Aged; Sepsis; Stress, Physiological; Surgical Procedures, Operative; Tumor Necrosis Factor-alpha

Leptin, an adipocyte-derived signaling factor, is a member of the IL-6 cytokine family. However there is no direct evidence of leptin stimulation of the acute phase protein (APP) synthesis which is typical for all other IL-6-like factors. The purpose of this study was to characterize the dynamics of circulating leptin in relation to ten APPs. We used postoperative septic patients as a model of cytokine network hyperstimulation and intensive APP reaction. The prospective study was performed on 22 patients with proven postoperative intraabdominal sepsis after large abdominal surgery. Plasma levels of leptin, TNF-alpha, IL-1beta, soluble IL-2 receptor (sIL-2R), IL-6 (ELISA analysis) and ten APPs (nephelometric analysis) were estimated. We have demonstrated a statistically significant elevation of plasma leptin concentrations in the septic group compared with healthy subjects (p<0.001). The correlation of plasma leptin and BMI during postoperative sepsis was diminished. The regression coefficient was the highest for leptin and CRP (r=0.48, p<0.05), and for leptin and alpha-1-antitrypsin (r=0.46, p<0.05) in the septic group. There was significant correlation between TNF-alpha and leptin (r=0.47, p<0.05) and between IL-6 and leptin (r=0.45, p<0.05) in septic patients. No significant correlation was found between leptin and "negative" APP and between leptin and IL-1beta. Leptin has thus been shown as an acute phase reactant with a potential hematopoietic, immunomodulatory and hepatocyte stimulating activity during the infectious and non-infectious stress response. The significant correlation between leptin and CRP and leptin and alpha-1-antitrypsin indicates that leptin can participate in APP synthesis regulation during a systemic inflammatory response.

Topics: Adult; Aged; Body Mass Index; C-Reactive Protein; Humans; Leptin; Male; Middle Aged; Predictive Value of Tests; Sepsis; Surgical Wound Infection; Tumor Necrosis Factor-alpha

Circulating leptin concentrations are raised in animal models of inflammation and sepsis. The purpose of this study was to determine the effect of sepsis on serum leptin concentration in humans and to examine the relationship between leptin and the metabolic consequences of sepsis. Resting energy expenditure, insulin sensitivity, and fasting serum leptin, plasma insulin, and cortisol concentrations were measured in 20 subjects with intra-abdominal sepsis and 20 healthy control subjects, before and during a 2-h period of euglycemic hyperinsulinemia. Fasting serum leptin concentrations were similar in septic and control subjects. In simple regression analysis, serum leptin concentrations correlated significantly with percent body fat in both septic patients (r = 0. 64, P < 0.005) and healthy subjects (r = 0.75, P < 0.0001). Multiple regression analyses additionally indicated that percent body fat, fasting plasma insulin, and plasma cortisol, but not sepsis, were significant and independent determinants of serum leptin concentration. No relationship between leptin and resting energy expenditure or insulin sensitivity was identifiable. A major metabolic role for leptin in human sepsis therefore appears unlikely.

Topics: Adipose Tissue; Adult; Biomarkers; Blood Glucose; Fasting; Female; Glucose Clamp Technique; Humans; Hydrocortisone; Insulin; Leptin; Male; Middle Aged; Proteins; Reference Values; Regression Analysis; Sepsis

Both leptin and interleukin-6 (IL-6) are hypersecreted in acute critical illness, such as sepsis. Leptin is produced by adipocytes, it inhibits appetite and stimulates the sympathetic nervous system, thereby reducing adipose mass. IL-6 is produced by immune cells and adipocytes, it reduces the production of other inflammatory cytokines and stimulates release of acute phase proteins by the liver, participating in the control of inflammation. Leptin inhibits, whereas IL-6 stimulates, the hypothalamic-pituitary-adrenal axis. While high IL-6 levels are associated with poor outcome in critically ill patients, the role of leptin in critical illness and its importance for survival are not known. To examine the relation between IL-6, leptin and cortisol in critical illness, we performed frequent 4 h plasma sampling in eight patients on day 1 of intensive care unit admission for acute sepsis. Sampling was repeated on days 3 and 5 in the five survivors. The levels of all three hormones were markedly elevated; there was a lack of the normal diurnal rhythmicity of leptin and IL-6 and a blunted diurnal rhythmicity of cortisol secretion. A strong negative correlation between mean 24 h plasma IL-6 and leptin was revealed. Although such a relationship could possibly be explained by the negative and positive effects of cortisol hypersecretion on each hormone respectively, a negative correlation between leptin and cortisol was detected, whereas there was no significant correlation between IL-6 and cortisol. Mean IL-6 values were higher (1389.5+/-644.9 vs. 658.8+/-250.5) and leptin levels were lower (2.73+/-1.1 vs. 26.5+/-11.6) in the non-survivors than in the survivors. These findings suggest that IL-6 is not the principal stimulus of leptin hypersecretion in critically ill patients with sepsis. The negative relation between IL-6 and leptin is of potential importance, as high IL-6 levels have been associated with poor outcome in critically ill patients, and relatively low leptin levels may impair sympathetic system and immune functions.

Topics: Circadian Rhythm; Critical Illness; Female; Humans; Hydrocortisone; Interleukin-6; Leptin; Male; Prospective Studies; Proteins; Sepsis