| 1. |
- Rönn, Tina, et al.
(författare)
-
Circulating triglycerides are associated with human adipose tissue DNA methylation of genes linked to metabolic disease
- 2023
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 32:11, s. 1875-1887
-
Tidskriftsartikel (refereegranskat)abstract
- Dysregulation of circulating lipids is a central element for the metabolic syndrome. However, it is not well established whether human subcutaneous adipose tissue is affected by or affect circulating lipids through epigenetic mechanisms. Hence, our aim was to investigate the association between circulating lipids and DNA methylation levels in human adipose tissue. DNA methylation and gene expression were analysed genome-wide in subcutaneous adipose tissue from two different cohorts, including 85 men and 93 women, respectively. Associations between DNA methylation and circulating levels of triglycerides, low-density lipoprotein, high-density lipoprotein and total cholesterol were analysed. Causal mediation analyses tested if adipose tissue DNA methylation mediates the effects of triglycerides on gene expression or insulin resistance. We found 115 novel associations between triglycerides and adipose tissue DNA methylation, e.g. in the promoter of RFS1, ARID2 and HOXA5 in the male cohort (P ≤ 1.1 × 10-7), and 63 associations, e.g. within the gene body of PTPRN2 and COL6A3 in the female cohort. We further connected these findings to altered mRNA expression levels in adipose tissue (e.g. HOXA5, IL11 and FAM45B). Interestingly, there was no overlap between methylation sites associated with triglycerides in men and the sites found in women, which points towards sex-specific effects of triglycerides on the epigenome. Finally, a causal mediation analysis provided support for adipose tissue DNA methylation as a partial mediating factor between circulating triglycerides and insulin resistance. This study identified novel epigenetic alterations in adipose tissue associated with circulating lipids. Identified epigenetic changes seem to mediate effects of triglycerides on insulin resistance.
|
|
| 2. |
- Rönn, Tina, et al.
(författare)
-
Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.
- 2015
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:13, s. 3792-3813
-
Tidskriftsartikel (refereegranskat)abstract
- Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed DNA methylation of ∼480,000 sites in human adipose tissue from 96 males and 94 females, and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1,050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of ageing in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2,825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with methylation of 711 sites, annotated to e.g. RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for metabolic diseases and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.
|
|
| 3. |
- Benrick, Anna, 1979, et al.
(författare)
-
Electroacupuncture mimics exercise-induced changes in skeletal muscle gene expression in polycystic ovary syndrome women.
- 2020
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:6, s. 2027-2041
-
Tidskriftsartikel (refereegranskat)abstract
- Autonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown.To identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS).Participants: In a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays.A single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q<0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q<0.20), and these changes correlated with altered expression of 101 genes (p<0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these two genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis.Our findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.
|
|
| 4. |
- Benrick, Anna, 1979-, et al.
(författare)
-
Electroacupuncture mimics exercise-induced changes in skeletal muscle gene expression in women with polycystic ovary syndrome
- 2020
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 105:6, s. 2027-2041
-
Tidskriftsartikel (refereegranskat)abstract
- ContextAutonomic nervous system activation mediates the increase in whole-body glucose uptake in response to electroacupuncture but the mechanisms are largely unknown.ObjectiveTo identify the molecular mechanisms underlying electroacupuncture-induced glucose uptake in skeletal muscle in insulin-resistant overweight/obese women with and without polycystic ovary syndrome (PCOS).Design/ParticipantsIn a case-control study, skeletal muscle biopsies were collected from 15 women with PCOS and 14 controls before and after electroacupuncture. Gene expression and methylation was analyzed using Illumina BeadChips arrays.ResultsA single bout of electroacupuncture restores metabolic and transcriptional alterations and induces epigenetic changes in skeletal muscle. Transcriptomic analysis revealed 180 unique genes (q < 0.05) whose expression was changed by electroacupuncture, with 95% of the changes towards a healthier phenotype. We identified DNA methylation changes at 304 unique sites (q < 0.20), and these changes correlated with altered expression of 101 genes (P < 0.05). Among the 50 most upregulated genes in response to electroacupuncture, 38% were also upregulated in response to exercise. We identified a subset of genes that were selectively altered by electroacupuncture in women with PCOS. For example, MSX1 and SRNX1 were decreased in muscle tissue of women with PCOS and were increased by electroacupuncture and exercise. siRNA-mediated silencing of these 2 genes in cultured myotubes decreased glycogen synthesis, supporting a role for these genes in glucose homeostasis.ConclusionOur findings provide evidence that electroacupuncture normalizes gene expression in skeletal muscle in a manner similar to acute exercise. Electroacupuncture might therefore be a useful way of assisting those who have difficulties performing exercise.
|
|
| 5. |
- Kokosar, Milana, et al.
(författare)
-
Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic and epigenetic factors may predispose women to polycystic ovary syndrome (PCOS), a common heritable disorder of unclear etiology. Here we investigated differences in genome-wide gene expression and DNA methylation in adipose tissue from 64 women with PCOS and 30 controls. In total, 1720 unique genes were differentially expressed (Q < 0.05). Six out of twenty selected genes with largest expression difference (CYP1B1, GPT), genes linked to PCOS (RAB5B) or type 2 diabetes (PPARG, SVEP1), and methylation (DMAP1) were replicated in a separate case-control study. In total, 63,213 sites (P < 0.05) and 440 sites (Q < 0.15) were differently methylated. Thirty differentially expressed genes had corresponding changes in 33 different DNA methylation sites. Moreover, a total number of 1913 pairs of differentially expressed "gene-CpG" probes were significantly correlated after correction for multiple testing and corresponded with 349 unique genes. In conclusion, we identified a large number of genes and pathways that are affected in adipose tissue from women with PCOS. We also identified specific DNA methylation pathways that may affect mRNA expression. Together, these novel findings show that women with PCOS have multiple transcriptional and epigenetic changes in adipose tissue that are relevant for development of the disease.
|
|
| 6. |
- Kokosar, Milana, et al.
(författare)
-
Erratum: Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome.
- 2016
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Scientific Reports 6: Article number: 22883; Published online: 15 March 2016; Updated: 09 May 2016 This Article contains errors. In Table 3, the text in the first row ‘Down-regulated genes’ was incorrectly given as ‘Up-regulated genes’. In addition, Fig. 2E was incorrectly labeled as Fig. 2ES. The correct Fig.
|
|
| 7. |
- Stener-Victorin, Elisabet, et al.
(författare)
-
Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
- 2024
-
Ingår i: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
|
|
