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- Bialesova, L, et al.
(författare)
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Epigenetic Regulation of PLIN 1 in Obese Women and its Relation to Lipolysis
- 2017
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1, s. 10152-
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Tidskriftsartikel (refereegranskat)abstract
- Increased adipocyte lipolysis links obesity to insulin resistance. The lipid droplet coating-protein Perilipin participates in regulation of lipolysis and is implicated in obesity. In the present study we investigate epigenetic regulation of the PLIN1 gene by correlating PLIN1 CpG methylation to gene expression and lipolysis, and functionally evaluating PLIN1 promoter methylation. PLIN1 CpG methylation in adipocytes and gene expression in white adipose tissue (WAT) was quantified in two cohorts by array. Basal lipolysis in WAT explants and adipocytes was quantified by measuring glycerol release. CpG-methylation of the PLIN1 promoter in adipocytes from obese women was higher as compared to never-obese women. PLIN1 promoter methylation was inversely correlated with PLIN1 mRNA expression and the lipolytic activity. Human mesenchymal stem cells (hMSCs) differentiated in vitro into adipocytes and harboring methylated PLIN1 promoter displayed decreased reporter gene activity as compared to hMSCs harboring unmethylated promoter. Treatment of hMSCs differentiated in vitro into adipocytes with a DNA methyltransferase inhibitor increased levels of PLIN1 mRNA and protein. In conclusion, the PLIN1 gene is epigenetically regulated and promoter methylation is inversely correlated with basal lipolysis in women suggesting that epigenetic regulation of PLIN1 is important for increased adipocyte lipolysis in insulin resistance states.
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| 2. |
- Dahlman, I, et al.
(författare)
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Adipose tissue pathways involved in weight loss of cancer cachexia
- 2010
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 102:10, s. 1541-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.
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| 3. |
- Dahlman, I, et al.
(författare)
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Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women
- 2017
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 312:6, s. E482-E494
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Tidskriftsartikel (refereegranskat)abstract
- The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3′-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.
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| 6. |
- Jiao, H, et al.
(författare)
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Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:10, s. 2980-2989
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Tidskriftsartikel (refereegranskat)abstract
- Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole-exome sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit β3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 control subjects with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 control subjects, rs2076349 showed strong association with obesity (P = 9.67 × 10−5; odds ratio 1.84). This variant was also associated with BMI and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. This gene may be involved in the development of excess body fat.
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