BackgroundSepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed.Methodology/Principal FindingsThe purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5–7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1β. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice.ConclusionsOur findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis.

The IL-1 system, recently shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men.

There is growing evidence that immune functions are linked to the regulation of body fat. Our studies of knockout mice indicate that both endogenous interleukin (IL)-6 and IL-1 can suppress mature-onset obesity. We now investigated whether four common polymorphisms of the IL6 and IL1 systems are associated with the fat mass measured with dual-energy X-ray absorptiometry (DXA) in elderly men (n = 3,014). The study subjects were from the Swedish part of the MrOS multicenter population study and 69-81 years of age. The IL6 −174 G>C (Minor allele frequency (MAF) = 48%) gene promoter polymorphism was associated with the primary outcome total fat mass (P = 0.006) and regional fat masses, but not with lean body mass. The IL1B −31T>C (MAF = 34%) polymorphism was also associated with total fat (P = 0.007) and regional fat masses, but not lean body mass. The IL-1 receptor antagonist (IL-1ra) gene (IL1RN) +2018 T>C (MAF = 27%) polymorphism (in linkage disequilibrium (LD) with a well-studied variable number tandem repeat of 86 base pair (bp)) and IL1B +3953 C>T (MAF = 26%) polymorphism were not associated with total fat mass. In conclusion, the IL-1 and IL-6 systems, shown to suppress mature-onset obesity in experimental animals, contain gene polymorphisms that are associated with fat, but not lean, mass in elderly men. Recent evidence indicates that parts of the immune system play a role for the appearance of obesity (1-4). Inflammationregulating cytokines such as interleukin (IL)-6 may suppress fat mass, as IL-6-deficient mice develop mature-onset obesity (1). Similarly, the IL-1-system has been shown to influence fat mass in mice, as IL-1 receptor I-deficient mice develop mature-onset obesity (2) and mice with IL-1 receptor antagonist (IL-1ra) deficiency become obesity-resistant (3). Moreover, combined IL-6 and IL-1 deficiency causes severe early-onset obesity in mice (4), and both IL-1 and IL-6 seems to enhance thermogenesis at the level of the hypothalamus (5).Several studies have shown that single-nucleotide polymorphisms (SNPs) in genes of the IL1 and IL6 systems are associated with changes in cytokine production and immune activity (6,7). Some comparatively small studies also indicate that the functional IL6 −174 G>C polymorphism is connected with increased surrogated parameters of fat mass, such as BMI and leptin levels (8,9). In addition, we recently showed that IL1 system polymorphisms are associated with fat mass in a young male population (10), and Um et al. reported an association between an IL1B polymorphism and BMI in a small non-population-based study of women (11). Finally, the serum levels of IL-1ra are positively correlated with BMI and serum leptin (12).In this study we have investigated four well-known polymorphisms in the genes of the IL1 and IL6 systems in relation to the primary outcome total body fat mass, as measured by dualenergy X-ray absorptiometry (DXA), in a large population of elderly Swedish men, MrOS Sweden (13). The allele and genotype frequencies of the studied polymorphisms are shown in...

ContextRegulation of fat mass appears to be associated with immune functions. Studies of knockout mice show that endogenous interleukin (IL)-6 can suppress mature-onset obesity.ObjectiveTo systematically investigate associations of single nucleotide polymorphisms (SNPs) near the IL-6 (IL6) and IL-6 receptor (IL6R) genes with body fat mass, in support for our hypothesis that variants of these genes can be associated with obesity.Design and Study SubjectsThe Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18-20 years old men (n=1 049), from the Gothenburg area (Sweden). Major findings were confirmed in two additional cohorts consisting of elderly men from the Osteoporotic Fractures in Men (MrOS) Sweden (n=2 851) and MrOS US (n=5 611) multicenter population-based studies.Main OutcomeThe genotype distributions and their association with fat mass in different compartments, measured with dual-energy X-ray absorptiometry (DXA).ResultsOut of 18 evaluated tag single nucleotide polymorphisms (SNPs) near the IL6 and IL6R genes, a recently identified SNP rs10242595 G/A [minor allele frequency (MAF) = 29%] 3′ of the IL6 gene was negatively associated with the primary outcome total body fat mass (effect size -0.11 standard deviation (SD) units/A allele, P=0.02). This negative association with fat mass was also confirmed in the combined MrOS Sweden and MrOS US cohorts (effect size -0.05 SD units/A allele; P=0.002). When all three cohorts were combined (n= 8 927, Caucasian subjects), rs10242595*A showed a negative association with total body fat mass (effect size -0.05 SD units/A allele, P<0.0002). Furthermore, the rs10242595*A was associated with low body mass index [(BMI, effect size -0.03, P<0.001)] and smaller regional fat masses. None of the other SNPs investigated in the GOOD study were reproducibly associated with body fat.ConclusionsThe IL6 gene polymorphism rs10242595*A is associated with decreased fat mass in three combined cohorts of 8 927 Caucasian men.