Short-Term High Fat Feeding Increases Organ Injury and Mortality After Polymicrobial Sepsis

Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Obesity (Impact Factor: 3.73). 02/2012; 20(10):1995-2002. DOI: 10.1038/oby.2012.40
Source: PubMed


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.


Available from: Basilia Zingarelli, Jul 15, 2014
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    • "The majority of studies in the literature induce DIO by short exposure to high fat diet (HFD) [11, 14, 33]. Kaplan et al. fed male C57BL/6 mice a HFD for 3 weeks and reported that septic obese mice had lower survival rates and severe lung injury compared to controls [33]. They further reported that lung and liver myeloperoxidase levels were greater in septic obese mice. "
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    ABSTRACT: Sepsis, a global health issue, is the most common cause of mortality in the intensive care unit. The aim of this study was to develop a new model of sepsis that investigates the impact of prolonged western diet (WD) induced obesity on the response to early sepsis. Male C57BL/6 mice were fed either a high fat WD or normal chow diet (NCD) for 6, 15, or 27 weeks. Septic obese mice at 15 and 27 weeks had significantly lower levels of lung myeloperoxidase (26.3 ± 3.80 U/mg tissue) compared to age matched ad lib (44.1 ± 2.86 U/mg tissue) and diet restricted (63.2 ± 5.60 U/mg tissue) controls. Low levels of lung inflammation were not associated with changes in hepatic cytokines and oxidative stress levels. Obese mice had significantly (P < 0.0001) larger livers compared to controls. Histological examination of the livers demonstrated that WD fed mice had increased inflammation with pronounced fat infiltration, steatosis, and hepatocyte ballooning. Using this model of prolonged exposure to high fat diet we have data that agree with recent clinical observations suggesting obese individuals are protected from sepsis-induced lung injury. This model will allow us to investigate the links between damage to the hepatic microcirculation, immune response, and lung injury.
    BioMed Research International 05/2014; 2014:719853. DOI:10.1155/2014/719853 · 2.71 Impact Factor
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    • "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]. Serum levels of these hormones are also altered in obese humans [14,15]. "
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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.
    BMC Infectious Diseases 08/2013; 13(1):377. DOI:10.1186/1471-2334-13-377 · 2.61 Impact Factor
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    ABSTRACT: Background The small intestine plays a crucial role in the pathophysiology of sepsis and has been referred to as the “motor” of the systemic inflammatory response. One proposed mechanism is that toxic gut-derived lipid factors, transported in mesenteric lymph, induce systemic injury and distant organ failure. However, the pathways involved are yet to be defined and the role of intestinal chylomicron assembly and secretion in transporting these lipid factors is unknown. Here we studied the outcome of sepsis in mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO), which exhibit a block in chylomicron assembly together with lipid malabsorption. Methodology/Principal Findings Mttp-IKO mice and controls underwent intratracheal injection with either Pseudomonas aeruginosa or sterile saline. Mttp-IKO mice exhibited decreased seven-day mortality, with 0/20 (0%) dying compared to 5/17 (29%) control mice (p<0.05). This survival advantage in Mttp-IKO mice, however, was not associated with improvements in pulmonary bacterial clearance or neutrophil infiltration. Rather, Mttp-IKO mice exhibited protection against sepsis-associated decreases in villus length and intestinal proliferation and were also protected against increased intestinal apoptosis, both central features in control septic mice. Serum IL-6 levels, a major predictor of mortality in human and mouse models of sepsis, were elevated 8-fold in septic control mice but remained unaltered in septic Mttp-IKO mice. Serum high density lipoprotein (HDL) levels were reduced in septic control mice but were increased in septic Mttp-IKO mice. The decreased levels of HDL were associated with decreased hepatic expression of apolipoprotein A1 in septic control mice. Conclusions/Significance These studies suggest that strategies directed at blocking intestinal chylomicron secretion may attenuate the progression and improve the outcome of sepsis through effects mediated by metabolic and physiological adaptations in both intestinal and hepatic lipid flux.
    PLoS ONE 11/2012; 7(11):e49159. DOI:10.1371/journal.pone.0049159 · 3.23 Impact Factor
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