| 1. |
- Franck, Niclas, et al.
(författare)
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Identification of adipocyte genes regulated by caloric intake
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Endocrine society. - 0021-972X .- 1945-7197. ; 96:2, s. E413-E418
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight. OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight. RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay. RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR. CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.
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| 2. |
- Hägg, Daniel, 1974, et al.
(författare)
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Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
- 2008
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Ingår i: International journal of molecular medicine. - 1107-3756 .- 1791-244X. ; 21:6, s. 697-704
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Tidskriftsartikel (refereegranskat)abstract
- Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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| 3. |
- Jernås, Margareta, 1961, et al.
(författare)
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MS risk genes are transcriptionally regulated in CSF leukocytes at relapse
- 2013
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1477-0970 .- 1352-4585. ; 19:4, s. 403-410
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Infiltrating T-helper cells, cytotoxic T-cells, B-cells and monocytes are thought to mediate the damage to myelin, oligodendrocytes and axons in multiple sclerosis (MS), which results in progressive disability. OBJECTIVE: The objective of this paper is to explore gene expression profiles of leukocytes in the cerebrospinal fluid (CSF) compartment of MS patients during relapse. METHODS: Global gene expression was analyzed by DNA microarray analysis of cells in CSF from MS patients and controls, and verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: Fifty percent of the recently described risk genes for MS and 28% of non-risk genes were differently expressed in MS patients compared to controls (χ(2)-test, p=7.7 × 10(-5)). Genes involved in T- and NK-cell processes were up-regulated, and genes involved in processes targeting innate immunity or B-cells were down-regulated in MS. Increased expression of EDN1 and CXCL11 and decreased expression of HMOX1 was verified with real-time PCR and increased expression of CXCL13 was verified with ELISA in CSF. CONCLUSION: DNA microarray analysis is useful in identifying differently expressed genes in CSF leukocytes, which may be important in MS in vivo. Our findings suggest that many of the risk genes for MS are differently expressed in the disease-mediating leukocytes that penetrate the blood-brain barrier.
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| 4. |
- Palsdottir, Vilborg, 1979, et al.
(författare)
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Postnatal deficiency of essential fatty acids in mice results in resistance to diet-induced obesity and low plasma insulin during adulthood
- 2011
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Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 1532-2823 .- 0952-3278. ; 84:3-4, s. 85-92
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to investigate the long-term metabolic effects of postnatal essential fatty acid deficiency (EFAD). Mouse dams were fed an EFAD diet or an isoenergetic control diet 4 days before delivery and throughout lactation. The pups were weaned to standard diet (STD) and were later subdivided into two groups: receiving high fat diet (HFD) or STD. Body composition, energy expenditure, food intake and leptin levels were analyzed in adult offspring. Blood glucose and plasma insulin concentrations were measured before and during a glucose tolerance test. EFAD offspring fed STD were leaner with lower plasma leptin and insulin concentrations compared to controls. EFAD offspring fed HFD were resistant to diet-induced obesity, had higher energy expenditure and lower levels of plasma leptin and insulin compared to controls. These results indicate that the fatty acid composition during lactation is important for body composition and glucose tolerance in the adult offspring.
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| 5. |
- Palsdottir, Vilborg, 1979, et al.
(författare)
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Prenatal essential fatty acid deficiency in mice results in long-term gender-specific effects on body weight and glucose metabolism
- 2011
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Ingår i: Molecular Medicine Reports. - : Spandidos Publications. - 1791-2997 .- 1791-3004. ; 4:4, s. 731-737
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Tidskriftsartikel (refereegranskat)abstract
- Essential fatty acids are important for normal growth and development in early life. However, the long-term effects of prenatal essential fatty acid deficiency (EFAD) on the adult metabolism remain to be determined. The aim of this study was to investigate the effects of an EFAD diet given to mice during late gestation on body weight and body composition, and metabolism in the adult offspring. Pregnant dams were given an EFAD or a control diet during the last 10 days of gestation. After delivery, all mice were fed normal chow and the body weight of the offspring was measured weekly. Furthermore, food intake, energy expenditure and intraperitoneal glucose tolera-nce were analysed in the adult offspring in addition to body composition (analysed by dual-energy X-ray absorptiometry), plasma levels of leptin, triglycerides and cholesterol. The body weight was lower in the EFAD offspring as compared to the controls during the first 4 weeks of age, and remained lower in the females throughout the study. Lean body mass and plasma leptin levels were also lower in the female EFAD offspring as compared to the controls. Male EFAD offspring were found to have higher fasting glucose and insulin levels as well as higher insulin levels during the glucose tolerance test compared to the controls. However, no differences were found in blood lipids, food intake or energy expenditure between EFAD and control mice of either gender. These results demonstrate that an EFAD diet given during the last 10 days of gestation results in long-term gender-specific effects on body weight and insulin sensitivity in the adult offspring.
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| 6. |
- Jernås, Margareta, 1961, et al.
(författare)
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Changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins in patients with critical illness.
- 2009
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 58:1, s. 102-8
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Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance develops rapidly during critical illness. The release of adipokines from adipose tissue is thought to play a key role in the development of insulin resistance, as are elevated levels of acute-phase proteins. The aim of this study was to identify changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins during critical illness. From 8 patients with subarachnoidal hemorrhage, consecutive blood samples and adipose tissue biopsies were obtained at 3 time points, twice during intensive care (1-2 days [IC1] and 7-9 days after subarachnoidal hemorrhage) and once after 8 months (recovery). The patients received a continuous insulin infusion to maintain normal glucose levels reflecting insulin resistance. The DNA microarray analysis showed increased zink-alpha2 glycoprotein (ZAG) and phospholipase A2, group IIA messenger RNA levels during intensive care compared with recovery (P < .05). Real-time polymerase chain reaction confirmed the increased expression of ZAG and phospholipase A2, group IIA. Plasma levels of ZAG, serum amyloid A, and C-reactive protein were higher at 7 to 9 days after subarachnoidal hemorrhage compared with either IC1 or recovery (P = .0001); and plasma levels of retinol-binding protein 4 and adiponectin were lower at IC1 compared with recovery (P = .05). The described changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins may influence the development of insulin resistance during critical illness.
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| 7. |
- Jernås, Margareta, 1961, et al.
(författare)
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Differences in gene expression and cytokine levels between newly diagnosed and chronic pediatric ITP.
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 122:10, s. 1789-92
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Tidskriftsartikel (refereegranskat)abstract
- Immune thrombocytopenia (ITP) is an autoimmune disease where platelets are destroyed prematurely. In the majority of children the disease resolves, but in some it becomes chronic. To investigate whether these 2 phases of the disease are molecularly similar or separate entities we performed DNA microarray analysis (GEO accession number: GSE46922) of T-cells from newly diagnosed children and children with chronic ITP. We found complete separation of the gene expression profiles between the 2 phases of the disease. Furthermore, the gene expression levels of several cytokines differed between the 2 phases of the disease. This was also reflected in plasma with increased levels of interleukin (IL)-16 and TNF-related weak inducer of apoptosis and lower levels of IL-4 in newly diagnosed compared with chronic ITP. Thus, our data indicate that chronic ITP in childhood is a separate disease entity, dissimilar in many aspects to the newly diagnosed phase.
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| 8. |
- Jernås, Margareta, 1961, et al.
(författare)
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Differential expression of T-cell genes in blood and bone marrow between ITP patients and controls
- 2013
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 109:1, s. 112-117
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Tidskriftsartikel (refereegranskat)abstract
- Primary immune thrombocytopenia (ITP) is an autoimmune disease characterised by premature platelet destruction in spleen, liver and bone marrow and a diminished production of platelets. T-cells are important in all forms of autoimmunity including ITP; however, very little is known about T-cells in organs where platelets are destroyed. Our aim was to investigate differences in gene expression in peripheral blood-derived T-cells and bone marrow-derived T-cells between ITP patients and controls. T-cells and subsequent RNA were isolated from blood and bone marrow from chronic ITP patients and healthy controls followed by DNA microarray analysis. There were 1554 differentially expressed genes in peripheral blood-derived T-cells and 976 in bone marrow-derived T-cells between ITP patients and controls and three genes were verified with real-time PCR. Using Gene Ontology functional enrichment analysis we found that genes involved in growth, development, migration, chemotaxis, adhesion and apoptosis were enriched in bone marrow-derived T-cells in ITP. Immune-related genes involved in T-helper cell differentiation, T-cell chemotaxis, migration, immunoglobulin-mediated immune response and classical and alternative pathway complement activation were also enriched in bone marrow-derived T-cells in ITP. Only 213 T-cell genes were differentially expressed in both blood and bone marrow between ITP patients and controls. In conclusion, our findings show that genes involved in major pathophysiologic pathways in ITP such as T-helper cell differentiation, autoantibody response and complement activation are altered in bone marrow-derived T-cells in ITP patients compared with controls. This further supports the concept that bone marrow is an important compartment in ITP.
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| 9. |
- Jernås, Margareta, 1961, et al.
(författare)
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MicroRNA regulate immune pathways in T-cells in multiple sclerosis (MS)
- 2013
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Ingår i: BMC Immunology. - : Springer Science and Business Media LLC. - 1471-2172. ; 14:32
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Tidskriftsartikel (refereegranskat)abstract
- Background: MicroRNA are small noncoding RNA molecules that are involved in the control of gene expression. To investigate the role of microRNA in multiple sclerosis (MS), we performed genome-wide expression analyses of mRNA and microRNA in T-cells from MS patients and controls.Methods: Heparin-anticoagulated peripheral blood was collected from MS-patients and healthy controls followed by isolation of T-cells. MicroRNA and RNA from T-cells was prepared and hybridized to Affymetrix miR 2.0 array and Affymetrix U133Plus 2.0 Human Genome array (Santa Clara, CA), respectively. Verifications were performed with real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA).Results: We identified 2,452 differentially expressed genes and 21 differentially expressed microRNA between MS patients and controls. By Kolmogorov-Smirnov test, 20 of 21 differentially expressed microRNA were shown to affect the expression of their target genes, many of which were involved in the immune system. Tumor necrosis factor ligand superfamily member 14 (TNFSF14) was a microRNA target gene significantly decreased in MS. The differential expression of mir-494, mir-197 and the predicted microRNA target gene TNFSF14 was verified by real-time PCR and ELISA.Conclusion: These findings indicate that microRNA may be important regulatory molecules in T-cells in MS.
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| 10. |
- Jernås, Margareta, 1961, et al.
(författare)
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MicroRNA regulate immunological pathways in T-cells in immune thrombocytopenia (ITP)
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 121:11, s. 2095-2098
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNA are small non-coding RNA molecules that regulate gene expression. To investigate the role of microRNA in ITP, we performed genome-wide expression analyses of mRNA and microRNA in T-cells from ITP patients and controls. We identified 1,915 regulated genes and 22 regulated microRNA that differed between ITP patients and controls. Seventeen of the 22 regulated microRNA were linked to changes in target gene expression; 57 of these target genes were associated with the immune system, e.g. T-cell activation and regulation of immunoglobulin production. CXCL13 and IL-21 were two microRNA target genes significantly increased in ITP. We could demonstrate increased plasma levels of CXCL13 and others have reported increased plasma levels of IL-21 in ITP. Thus, regulated microRNA were significantly associated with both gene and protein expression of molecules in immunological pathways. We suggest that microRNA may be important regulatory molecules involved in the loss of tolerance in ITP.
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