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- Ekstrom, M, et al.
(författare)
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Systemic inflammation activates the nuclear factor-kappaB regulatory pathway in adipose tissue
- 2010
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 299:2, s. E234-E240
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue (AT) is a store of energy but also an endocrine organ with the capacity to produce and release proinflammatory mediators into the circulation. The mechanism that may trigger human AT inflammation on a cellular level still remains largely unknown. The aim of this study was to investigate whether an acute systemic inflammation increases AT inflammatory activity, focused on innate immunity. Open heart surgery results in an extensive acute systemic inflammation. Therefore, we investigated the in vivo gene expression and production of inflammatory mediators in omental and subcutaneous AT stimulated by surgery. Biopsies from omental and subcutaneous AT were collected before and after cardiopulmonary bypass. Blood samples were collected at the same time as the AT biopsies and plasma IL-6 levels were measured with ELISA. RT-PCR was used for quantification of relative AT gene expression. To verify the gene expression results on a protein level, we used immunohistochemistry and microdialysis. After surgery, in both omental and subcutaneous AT, there was a strong upregulation of nuclear factor-κB-regulated genes, e.g., chemokine ligand-2, E-selectin, IL-1β, IL-6, IL-8, and Toll-like receptor-2. Immunohistochemistry showed staining for E-selectin associated with a high number of macrophages in close contact with and in the vascular wall. Increased levels of IL-6 were detected in microdialysate from subcutaneous AT. In conclusion, we present the novel finding that this model of inflammation induced a strong inflammatory response in both omental and subcutaneous AT including adhesion of macrophages to an activated endothelium and release of IL-6 from AT interstitium. It can be hypothesized that AT exerts a modulatory effect on innate immunity in humans.
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- Greco, D, et al.
(författare)
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Gene expression in human NAFLD
- 2008
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Ingår i: American journal of physiology. Gastrointestinal and liver physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 294:5, s. G1281-G1287
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Tidskriftsartikel (refereegranskat)abstract
- Despite the high prevalence of nonalcoholic fatty liver disease (NAFLD), little is known of its pathogenesis based on study of human liver samples. By the use of Affymetrix GeneChips (17,601 genes), we investigated gene expression in the human liver of subjects with extreme steatosis due to NAFLD without histological signs of inflammation (liver fat 66.0 ± 6.8%) and in subjects with low liver fat content (6.4 ± 2.7%). The data were analyzed by using sequence-based reannotation of Affymetrix probes and a robust model-based normalization method. We identified genes involved in hepatic glucose and lipid metabolism, insulin signaling, inflammation, coagulation, and cell adhesion to be significantly associated with liver fat content. In addition, genes involved in ceramide signaling (MAP2K4) and metabolism (UGCG) were found to be positively associated with liver fat content. Genes involved in lipid metabolism (PLIN, ACADM), fatty acid transport (FABP4, CD36), amino acid catabolism (BCAT1), and inflammation (CCL2) were validated by real-time PCR and were found to be upregulated in subjects with high liver fat content. The data show that multiple changes in gene expression characterize simple steatosis.
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| 6. |
- Kolak, Maria, et al.
(författare)
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Adipose tissue inflammation and increased ceramide content characterize subjects with high liver fat content independent of obesity
- 2007
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:8, s. 1960-1968
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We sought to determine whether adipose tissue is inflamed in individuals with increased liver fat (LFAT) independently of obesity.RESEARCH DESIGN AND METHODS: A total of 20 nondiabetic, healthy, obese women were divided into normal and high LFAT groups based on their median LFAT level (2.3 +/- 0.3 vs. 14.4 +/- 2.9%). Surgical subcutaneous adipose tissue biopsies were studied using quantitative PCR, immunohistochemistry, and a lipidomics approach to search for putative mediators of insulin resistance and inflammation. The groups were matched for age and BMI. The high LFAT group had increased insulin (P = 0.0025) and lower HDL cholesterol (P = 0.02) concentrations.RESULTS: Expression levels of the macrophage marker CD68, the chemokines monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha, and plasminogen activator inhibitor-1 were significantly increased, and those of peroxisome proliferator-activated receptor-gamma and adiponectin decreased in the high LFAT group. CD68 expression correlated with the number of macrophages and crown-like structures (multiple macrophages fused around dead adipocytes). Concentrations of 154 lipid species in adipose tissue revealed several differences between the groups, with the most striking being increased concentrations of triacylglycerols, particularly long chain, and ceramides, specifically Cer(d18:1/24:1) (P = 0.01), in the high LFAT group. Expression of sphingomyelinases SMPD1 and SMPD3 were also significantly increased in the high compared with normal LFAT group.CONCLUSIONS: Adipose tissue is infiltrated with macrophages, and its content of long-chain triacylglycerols and ceramides is increased in subjects with increased LFAT compared with equally obese subjects with normal LFAT content. Ceramides or their metabolites could contribute to adverse effects of long-chain fatty acids on insulin resistance and inflammation.
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| 7. |
- Kolak, Maria, et al.
(författare)
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Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue
- 2012
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation and increased ceramide concentrations characterise adipose tissue of obese women with high liver fat content compared to equally obese women with normal liver fat content. The present study characterises enzymes involved in ceramide metabolism in subcutaneous and intra-abdominal adipose tissue.METHODS: Pathways leading to increased ceramide concentrations in inflamed versus non-inflamed adipose tissue were investigated by quantifying expression levels of key enzymes involved in ceramide metabolism. Sphingomyelinases (sphingomyelin phosphodiesterases SMPD1-3) were investigated further using immunohistochemistry to establish their location within adipose tissue, and their mRNA expression levels were determined in subcutaneous and intra-abdominal adipose tissue from both non-obese and obese subject.RESULTS: Gene expression levels of sphingomyelinases, enzymes that hydrolyse sphingomyelin to ceramide, rather than enzymes involved in de novo ceramide synthesis, were higher in inflamed compared to non-inflamed adipose tissue of obese women (with high and normal liver fat contents respectively). Sphingomyelinases were localised to both macrophages and adipocytes, but also to blood vessels and to extracellular regions surrounding vessels within adipose tissue. Expression levels of SMPD3 mRNA correlated significantly with concentrations of different ceramides and sphingomyelins. In both non-obese and obese subjects SMPD3 mRNA levels were higher in the more inflamed intra-abdominal compared to the subcutaneous adipose tissue depot.CONCLUSIONS: Generation of ceramides within adipose tissue as a result of sphingomyelinase action may contribute to inflammation in human adipose tissue.
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| 8. |
- Kolak, M., et al.
(författare)
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Molecular typing of the bacterial flora in sputum of cystic fibrosis patients
- 2003
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Ingår i: International Journal of Medical Microbiology. - : Elsevier BV. - 1438-4221 .- 1618-0607. ; 293:4, s. 309-317
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Tidskriftsartikel (refereegranskat)abstract
- Despite recent advances in therapy, lower airway infections remain the major cause of morbidity and mortality in cystic fibrosis (CF) patients. Bacterial colonisation of the lower airways in CF is limited to a few bacterial species, commonly Staphylococcus aureus, Pseudomonas aeruginosa and Haemophilus influenzae. Burkholderia cepacia colonisation is much rarer, but it has been thought to be associated with more advanced lung disease and increased mortality. A rapid characterisation of the bacterial flora in sputum of CF patients is of great importance for proper treatment. The aim of this study was to establish bacterial profiles and to identify pathogenic bacteria in respiratory specimens by means of molecular methods including temporal temperature gradient gel electrophoresis (TTGE) and DNA sequencing of PCR amplicons derived from 16S rDNA variable V3 and V6 regions. Sputa of 13 CF patients (7 males/6 females, age 19-59 years) collected at the Stockholm CF centre were analysed. TTGE revealed the presence of complex bacterial profiles in all samples. The V3 and V6 PCR amplicons were cloned and sequenced by real-time DNA PyrosequencingTM. DNA from Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa, respectively, was identified together with sequences from normal oral cavity flora. The results were in reasonable agreement with those obtained by conventional bacterial culture, considering that only known CF pathogens are included in routine reports. However, the methodology seems too elaborate to be introduced into daily routine.
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| 10. |
- Sjögren, Per, et al.
(författare)
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Functional changes in adipose tissue in a randomised controlled trial of physical activity
- 2012
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Ingår i: Lipids in Health and Disease. - 1476-511X. ; 11, s. 80-
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Tidskriftsartikel (refereegranskat)abstract
- Background: A sedentary lifestyle predisposes to cardiometabolic diseases. Lifestyle changes such as increased physical activity improve a range of cardiometabolic risk factors. The objective of this study was to examine whether functional changes in adipose tissue were related to these improvements. Methods: Seventy-three sedentary, overweight (mean BMI 29.9 +/- 3.2 kg/m(2)) and abdominally obese, but otherwise healthy men and women (67.6 +/- 0.5 years) from a randomised controlled trial of physical activity on prescription over a 6-month period were included (control n = 43, intervention n = 30). Detailed examinations were carried out at baseline and at follow-up, including fasting blood samples, a comprehensive questionnaire and subcutaneous adipose tissue biopsies for fatty acid composition analysis (n = 73) and quantification of mRNA expression levels of 13 candidate genes (n = 51), including adiponectin, leptin and inflammatory cytokines. Results: At follow-up, the intervention group had a greater increase in exercise time (+ 137 min/week) and a greater decrease in body fat mass (-1.5 kg) compared to the control subjects (changes of 0 min/week and -0.5 kg respectively). Circulating concentrations of adiponectin were unchanged, but those of leptin decreased significantly more in the intervention group (-1.8 vs - 1.1 ng/mL for intervention vs control, P < 0.05). The w6-polyunsaturated fatty acid content, in particular linoleic acid (18:2w6), of adipose tissue increased significantly more in the intervention group, but the magnitude of the change was small (+ 0.17 vs + 0.02 percentage points for intervention vs control, P < 0.05). Surprisingly leptin mRNA levels in adipose tissue increased in the intervention group (+ 107% intervention vs -20% control, P < 0.05), but changes in expression of the remaining genes did not differ between the groups. Conclusions: After a 6-month period of increased physical activity in overweight elderly individuals, circulating leptin concentrations decreased despite increased levels of leptin mRNA in adipose tissue. Otherwise, only minor changes occurred in adipose tissue, although several improvements in metabolic parameters accompanied the modest increase in physical activity.
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