Gut microbiota-derived lipopolysaccharide uptake and trafficking to adipose tissue: implications for inflammation and obesity.

The composition of the gut microbiota and excessive ingestion of high-fat diets (HFD) are considered to be important factors for development of obesity. In this review we describe a coherent mechanism of action for the development of obesity, which involves the composition of gut microbiota, HFD, low-grade inflammation, expression of fat translocase and scavenger receptor CD36, and the scavenger receptor class B type 1 (SR-BI). SR-BI binds to both lipids and lipopolysaccharide (LPS) from Gram-negative bacteria, which may promote incorporation of LPS in chylomicrons (CMs). These CMs are transported via lymph to the circulation, where LPS is transferred to other lipoproteins by translocases, preferentially to HDL. LPS increases the SR-BI binding, transcytosis of lipoproteins over the endothelial barrier,and endocytosis in adipocytes. Especially large size adipocytes with high metabolic activity absorb LPS-rich lipoproteins. In addition, macrophages in adipose tissue internalize LPS-lipoproteins. This may contribute to the polarization from M2 to M1 phenotype, which is a consequence of increased LPS delivery into the tissue during hypertrophy. In conclusion, evidence suggests that LPS is involved in the development of obesity as a direct targeting molecule for lipid delivery and storage in adipose tissue.

The role of glutathione S-transferase and claudin-1 gene polymorphisms in contact sensitization: a cross-sectional study.

BACKGROUND: Contact sensitization is frequent in the general population and arises from excessive or repeated skin exposure to chemicals and metals. However, little is known about its genetic susceptibility. OBJECTIVES: To determine the role of polymorphisms of glutathione S-transferase (GST) genes and the claudin-1 gene (CLDN1) on the risk of contact sensitization, taking common filaggrin gene (FLG) mutations into account. METHODS: In total, 3471 adult Danes from the general population were standard patch tested and filled out a questionnaire on their general health. They were genotyped for the following polymorphisms: GSTM1 and GSTT1 deletion, GSTP1 single nucleotide polymorphism (SNP) rs1695, four CLDN1 SNPs (rs893051, rs9290927, rs9290929 and rs17501010) and the FLG null mutations R501X and 2282del4. RESULTS: In individuals without ear piercings, a higher prevalence of nickel sensitization was found in those with the minor allele of CLDN1 SNP rs9290927 (P(trend)=0·013). For CLDN1 rs17501010, contact sensitization to organic compounds was associated with the major allele (P(trend)=0·031). The risk pattern was also identified for self-reported nickel dermatitis (P(trend)=0·011). The fragrance sensitization prevalence differed in a pairwise comparison of the CLDN1 rs893051 SNP genotypes (P=0·022), with the minor allele being associated with a higher prevalence. The associations were confirmed in logistic regression analyses. CONCLUSIONS: The CLDN1 polymorphisms rs9290927, rs893051 and rs17501010 were associated, respectively, with nickel contact sensitization in individuals without ear piercings, contact sensitization to fragrances, and with both organic compounds and nickel contact dermatitis. We could not find associations between GST gene polymorphisms and contact sensitization. FLG mutations did not affect the observed associations.

A proposed potential role for increasing atmospheric CO2 as a promoter of weight gain and obesity.

Human obesity has evolved into a global epidemic. Interestingly, a similar trend has been observed in many animal species, although diet composition, food availability and physical activity have essentially remained unchanged. This suggests a common factor-potentially an environmental factor affecting all species. Coinciding with the increase in obesity, atmospheric CO2 concentration has increased more than 40%. Furthermore, in modern societies, we spend more time indoors, where CO2 often reaches even higher concentrations. Increased CO2 concentration in inhaled air decreases the pH of blood, which in turn spills over to cerebrospinal fluids. Nerve cells in the hypothalamus that regulate appetite and wakefulness have been shown to be extremely sensitive to pH, doubling their activity if pH decreases by 0.1 units. We hypothesize that an increased acidic load from atmospheric CO2 may potentially lead to increased appetite and energy intake, and decreased energy expenditure, and thereby contribute to the current obesity epidemic.

Insulin resistance as a predictor of incident asthma-like symptoms in adults.

BACKGROUND: There is accumulating evidence that obesity is associated with an increased risk of asthma. It has been hypothesized that insulin resistance may be involved in obesity-induced asthma, but till date there is no prospective data on this issue. OBJECTIVE: To investigate the association of obesity and insulin resistance with the incidence of asthma-like symptoms in adults. METHODS: Out of a random sample of 12 934 persons from a general population, 6784 (52.5%) were included and participated in a health examination in 1999-2001. After 5 years they were re-invited and 4516 (66.6%) participated at follow-up. At baseline three obesity measures were considered: body mass index, waist circumference, and waist-to-hip ratio. In addition, fasting glucose and insulin were measured for determination of insulin resistance. Information on asthma-like symptoms at baseline and follow-up were obtained by questionnaires. A total of 3441 participants defined as non-asthmatic at baseline and with complete information on all the considered variables were included in the analyses. Data were controlled for confounding by sex, age, social status, and smoking. RESULTS: All obesity measures were associated with incident wheezing and asthma-like symptoms. In addition, insulin resistance was associated with incident wheezing [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38-2.54] and asthma-like symptoms (OR 1.61, 95% CI 1.23-2.10). The effect of insulin resistance was stronger than that of obesity and was independent of sex. CONCLUSION: We found that insulin resistance was associated with an increased risk of developing asthma-like symptoms. This finding supports the hypothesis that obesity and asthma may be linked through inflammatory pathways also involved in insulin resistance.

The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance?

There is increasing epidemiological evidence that obesity increases the risk of asthma, atopic, and autoimmune diseases. We hypothesize that the increase in these diseases is caused, at least in part, by decreased immunological tolerance as a consequence of immunological changes induced by adipokines (e.g. leptin and adiponectin) and cytokines [e.g. interleukin 6 (IL6) and tumor necrosis factor alpha (TNFalpha)] secreted by white adipose tissue. The increasing body weight increases the levels of circulating IL6, leptin, and TNFalpha. IL6 and leptin down-regulate the activity of regulatory T-lymphocytes (Tregs). Additionally, adiponectin, which decreases with increasing obesity, down-regulates the secretion of IL10 from macrophages and adipocytes. These changes in IL6, leptin, and IL10 decrease the regulatory effect of Tregs resulting in decreased immunological tolerance to antigens. In pregnant women, these obesity-induced immunological changes might be transmitted to the fetus by epigenetic inheritance thereby increasing the risk of atopic disease. We propose that obesity results in immunological changes resulting in decreased immunological tolerance to antigens and skewing of the immune system towards a Th2 cytokine profile increasing the risk of allergy and other immune-mediated diseases. Furthermore, this hypothesis offers a unifying explanation for the observation that older siblings appear to confer protection against atopic diseases, preeclampsia, and certain autoimmune diseases. More studies are definitely needed to explore further the immunological effects of obesity and its possible effects on allergic disease.

Viruses as the causative agent related to 'dampness' and the missing link between allergen exposure and onset of allergic disease.

UNLABELLED: Asthma and asthma-like symptoms occur more often among people living in humid indoor climates. It has been postulated that the higher concentration of allergens in these environments is the cause for the increase in the number of affected people. However, poor correlations between allergen concentration and symptoms indicate a missing link between allergen exposure and onset of asthma. Respiratory viruses have been identified in up to 85% cases of asthma or exacerbations of asthma. The missing link between respiratory diseases and humid indoor climates could therefore be attributed to viruses. The infectious effectiveness of respiratory viruses depends strongly on the environment where the viruses are spread. For respiratory viruses, survival and infectivity are dependent on temperature and relative humidity. A direct link between virus-induced inflammation and the asthmatogenic process has been proposed. Therefore, a more effective spreading of viral infections in damp indoor climates is likely to represent the main cause for the increased prevalence of asthma in these environments. Moreover, the incidence of viral infections is higher in patients with asthma compared with that in control subjects. Therefore, a humid indoor climate could also represent a higher risk for persons already sensitized to one or more allergens. PRACTICAL IMPLICATIONS: In epidemiological studies where the relationship between moisture in the indoor climate, respiratory symptoms and exposure to allergens is investigated it will be necessary to analyze the role of respiratory viruses in relation to respiratory symptoms. Today, the necessary techniques to address the presence of viruses [e.g. polymerase chain reaction (PCR), antibodies] are highly sensitive. In order to further our understanding of why the frequency of asthma and atopic diseases is still increasing, it is mandatory to implement these methods.

Residential exposure to plasticizers and its possible role in the pathogenesis of asthma.

The plasticizer di(2-ethylhexyl) phthalate (DEHP) is widely used in building materials. DEHP is identified as the major plasticizer exposure in dwellings. We provide evidence that inhalation exposure to DEHP as aerosols adsorbed to particulate matter is as important, or more important, than vapor phase exposure. The particulate inhalation exposure to DEHP is considered to be significant due to its low clearance and extensive penetration into the pulmonary region. DEHP is capable of creating high local concentrations in the airways at the deposition site with subsequent local effects. The proposed mechanism of effect states that mono(2-ethylhexyl) phthalate (MEHP), the primary hydrolysis product of DEHP, mimics the inducing prostaglandins (PG) PGD(2), 9alpha,11betaPGF2, and PGF2alpha, and thromboxanes in the lungs, thereby increasing the risk of inducing inflammation in the airways, which is a characteristic of asthma.