| 1. |
- Brøns, Charlotte, et al.
(författare)
-
Deoxyribonucleic Acid Methylation and Gene Expression of PPARGC1A in Human Muscle Is Influenced by High-Fat Overfeeding in a Birth-Weight-Dependent Manner.
- 2010
-
Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 95, s. 3048-3056
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Low birth weight (LBW) and unhealthy diets are risk factors of metabolic disease including type 2 diabetes (T2D). Genetic, nongenetic, and epigenetic data propose a role of the key metabolic regulator peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PPARGC1A) in the development of T2D. Objective: Our objective was to investigate gene expression and DNA methylation of PPARGC1A and coregulated oxidative phosphorylation (OXPHOS) genes in LBW and normal birth weight (NBW) subjects during control and high-fat diets. Design, Subjects, and Main Outcome Measures: Twenty young healthy men with LBW and 26 matched NBW controls were studied after 5 d high-fat overfeeding (+50% calories) and after a control diet in a randomized manner. Hyperinsulinemic-euglycemic clamps were performed and skeletal muscle biopsies excised. DNA methylation and gene expression were measured using bisulfite sequencing and quantitative real-time PCR, respectively. Results: When challenged with high-fat overfeeding, LBW subjects developed peripheral insulin resistance and reduced PPARGC1A and OXPHOS (P < 0.05) gene expression. PPARGC1A methylation was significantly higher in LBW subjects (P = 0.0002) during the control diet. However, PPARGC1A methylation increased in only NBW subjects after overfeeding in a reversible manner. DNA methylation of PPARGC1A did not correlate with mRNA expression. Conclusions: LBW subjects developed peripheral insulin resistance and decreased gene expression of PPARGC1A and OXPHOS genes when challenged with fat overfeeding. The extent to which our finding of a constitutively increased DNA methylation in the PPARGC1A promoter in LBW subjects may contribute needs to be determined. We provide the first experimental support in humans that DNA methylation induced by overfeeding is reversible.
|
|
| 2. |
- Jacobsen, Stine C., et al.
(författare)
-
Young men with low birthweight exhibit decreased plasticity of genome-wide muscle DNA methylation by high-fat overfeeding
- 2014
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 57:6, s. 1154-1158
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The association between low birthweight (LBW) and risk of developing type 2 diabetes may involve epigenetic mechanisms, with skeletal muscle being a prime target tissue. Differential DNA methylation patterns have been observed in single genes in muscle tissue from type 2 diabetic and LBW individuals, and we recently showed multiple DNA methylation changes during short-term high-fat overfeeding in muscle of healthy people. In a randomised crossover study, we analysed genome-wide DNA promoter methylation in skeletal muscle of 17 young LBW men and 23 matched normal birthweight (NBW) men after a control and a 5 day high-fat overfeeding diet. Methods DNA methylation was measured using Illumina's Infinium BeadArray covering 27,578 CpG sites representing 14,475 different genes. Results After correction for multiple comparisons, DNA methylation levels were found to be similar in the LBW and NBW groups during the control diet. Whereas widespread DNA methylation changes were observed in the NBW group in response to high-fat overfeeding, only a few methylation changes were seen in the LBW group (chi(2), p < 0.001). Conclusions/interpretation Our results indicate lower DNA methylation plasticity in skeletal muscle from LBW vs NBW men, potentially contributing to understanding the link between LBW and increased risk of type 2 diabetes.
|
|
| 3. |
- Grunnet, Louise G., et al.
(författare)
-
Regulation and Function of FTO mRNA Expression in Human Skeletal Muscle and Subcutaneous Adipose Tissue
- 2009
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 58:10, s. 2402-2408
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Common variants in FTO (the fat mass- and obesity-associated gene) associate with obesity and type 2 diabetes. The regulation and biological function of FTO mRNA expression in target tissue is unknown. We investigated the genetic and nongenetic regulation of FTO mRNA in skeletal muscle and adipose tissue and their influence on in vivo glucose and fat metabolism. RESEARCH DESIGN AND METHODS-The FTO rs9939609 polymorphism was genotyped in two twin cohorts: 1) 298 elderly twins aged 62-83 years with glucose tolerance ranging from normal to type 2 diabetes and 2) 196 young (25-32 years) and elderly (58-66 years) nondiabetic twins examined by a hyperinsulinemic-euglycemic clamp including indirect calorimetry. FTO mRNA expression was determined in subcutaneous adipose tissue (n = 226) and skeletal muscle biopsies (n = 158). RESULTS-Heritability of FTO expression in both tissues was low, and FTO expression was not influenced by FTO rs9939609 genotype. FTO mRNA expression in skeletal muscle was regulated by age and sex, whereas age and BMI were predictors of adipose tissue FTO mRNA expression. FTO mRNA expression in adipose tissue was associated with an atherogenic lipid profile. In skeletal muscle, FTO mRNA expression was negatively associated to fat and positively to glucose oxidation rates as well as positively correlated with expression of genes involved in oxidative phosphorylation including PGC1 alpha. CONCLUSIONS-The heritability of FTO expression in adipose tissue and skeletal muscle is low and not influenced by obesity-associated FTO genotype. The age-dependent decline in FTO expression is associated with peripheral defects of glucose and fat metabolism. Diabetes 58:2402-2408, 2009
|
|
| 4. |
- Koeck, Thomas, et al.
(författare)
-
A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
- 2011
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 13:1, s. 80-91
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.
|
|
| 5. |
- Ling, Charlotte, et al.
(författare)
-
Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle.
- 2007
-
Ingår i: The Journal of clinical investigation. - 0021-9738. ; 117:11, s. 3427-35
-
Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance.
|
|
| 6. |
- Ling, Charlotte, et al.
(författare)
-
Multiple environmental and genetic factors influence skeletal muscle PGC-1alpha and PGC-1beta gene expression in twins.
- 2004
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 114:10, s. 1518-1526
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic and environmental factors contribute to age-dependent susceptibility to type 2 diabetes. Recent studies have reported reduced expression of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) and PGC-1ß genes in skeletal muscle from type 2 diabetic patients, but it is not known whether this is an inherited or acquired defect. To address this question we studied expression of these genes in muscle biopsies obtained from young and elderly dizygotic and monozygotic twins without known diabetes before and after insulin stimulation and related the expression to a Gly482Ser variant in the PGC-1{alpha} gene. Insulin increased and aging reduced skeletal muscle PGC-1{alpha} and PGC-1ß mRNA levels. This age-dependent decrease in muscle gene expression was partially heritable and influenced by the PGC-1{alpha} Gly482Ser polymorphism. In addition, sex, birth weight, and aerobic capacity influenced expression of PGC-1{alpha} in a complex fashion. Whereas expression of PGC-1{alpha} in muscle was positively related to insulin-stimulated glucose uptake and oxidation, PGC-1ß expression was positively related to fat oxidation and nonoxidative glucose metabolism. We conclude that skeletal muscle PGC-1{alpha} and PGC-1ß expression are stimulated by insulin and reduced by aging. The data also suggest different regulatory functions for PGC-1{alpha} and PGC-1ß on glucose and fat oxidation in muscle cells. The finding that the age-dependent decrease in the expression of these key genes regulating oxidative phosphorylation is under genetic control could provide an explanation by which an environmental trigger (age) modifies genetic susceptibility to type 2 diabetes.
|
|
| 7. |
- Nilsson, Emma A, et al.
(författare)
-
Genetic and Nongenetic Regulation of CAPN10 mRNA Expression in Skeletal Muscle.
- 2005
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 54:10, s. 3015-3020
-
Tidskriftsartikel (refereegranskat)abstract
- The gene encoding calpain-10 (CAPN10) has been identified as a candidate gene for type 2 diabetes. Our aim was to study the impact of genetic (heritability and polymorphisms) and nongenetic (insulin, free fatty acids, and age) factors on CAPN10 mRNA expression in skeletal muscle using two different study designs. Muscle biopsies were obtained before and after hyperinsulinemic-euglycemic clamps from 166 young and elderly monozygotic and dizygotic twins as well as from 15 subjects with normal (NGT) or impaired glucose tolerance (IGT) exposed to an Intralipid infusion. We found hereditary effects on both basal and insulin-exposed CAPN10 mRNA expression. Carriers of the type 2 diabetes–associated single nucleotide polymorphism (SNP)-43 G/G genotype had reduced CAPN10 mRNA levels compared with subjects carrying the SNP-43 A-allele. Age had no significant influence on CAPN10 mRNA levels. Insulin had no significant effect on CAPN10 mRNA levels, neither in the twins nor in the basal state of the Intralipid study. However, after a 24-h infusion of Intralipid, we noted a significant increase in CAPN10 mRNA in response to insulin in subjects with NGT but not in subjects with IGT. In conclusion, we provide evidence that mRNA expression of CAPN10 in skeletal muscle is under genetic control. Glucose-tolerant but not glucose-intolerant individuals upregulate their CAPN10 mRNA levels in response to prolonged exposure to fat.
|
|
| 8. |
- Nilsson, Emma, et al.
(författare)
-
Differential DNA Methylation and Expression of miRNAs in Adipose Tissue From Twin Pairs Discordant for Type 2 Diabetes
- 2021
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 70:10, s. 2402-2418
-
Tidskriftsartikel (refereegranskat)abstract
- The prevalence of type 2 diabetes (T2D) is increasing worldwide, but current treatments have limitations. miRNAs may play a key role in the development of T2D and can be targets for novel therapies. Here, we examined whether T2D is associated with altered expression and DNA methylation of miRNAs using adipose tissue from 14 monozygotic twin pairs discordant for T2D. Four members each of the miR-30 and let-7-families were downregulated in adipose tissue of subjects with T2D versus control subjects, which was confirmed in an independent T2D case-control cohort. Further, DNA methylation of five CpG sites annotated to gene promoters of differentially expressed miRNAs, including miR-30a and let-7a-3, was increased in T2D versus control subjects. Luciferase experiments showed that increased DNA methylation of the miR-30a promoter reduced its transcription in vitro. Silencing of miR-30 in adipocytes resulted in reduced glucose uptake and TBC1D4 phosphorylation; downregulation of genes involved in demethylation and carbohydrate/lipid/amino acid metabolism; and upregulation of immune system genes. In conclusion, T2D is associated with differential DNA methylation and expression of miRNAs in adipose tissue. Downregulation of the miR-30 family may lead to reduced glucose uptake and altered expression of key genes associated with T2D.
|
|
| 9. |
- Nilsson, Emma, et al.
(författare)
-
Regulation of skeletal muscle PPAR delta mRNA expression in twins
- 2007
-
Ingår i: Journal of Physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 584:3, s. 1011-1017
-
Tidskriftsartikel (refereegranskat)abstract
- Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism in a complex and to some extent unknown manner. Our aim was to study the impact of different factors on PPAR delta mRNA expression in human skeletal muscle on one side, and the impact of PPAR delta mRNA expression on these factors, including glucose and lipid metabolism, aerobic capacity, fibre type composition and lipid profile, on the other side. PPAR delta mRNA levels were quantified by real-time PCR in muscle biopsies from 176 young and elderly monozygotic and dizygotic twins. Young twins had significantly increased PPAR delta mRNA levels compared with elderly twins. A 2 h hyperinsulinaemic euglycaemic clamp had no significant effect on PPAR delta mRNA levels. Biometric models were calculated for basal PPAR delta mRNA expression to estimate the degree of genetic versus environmental influence. In both young and elderly twins there was a substantial genetic component influencing basal PPAR delta mRNA levels. In a regression model, the muscle PPAR delta mRNA expression was correlated to birth weight, central adiposity and age. The level of PPAR delta mRNA was also positively correlated with markers for oxidative muscle fibres. However, in this apparently healthy study population, we found no correlations between PPAR delta mRNA expression and aerobic capacity, lipid profile or glucose and lipid metabolism. In conclusion, we provide evidence that mRNA expression of PPAR delta in human skeletal muscle is under genetic control but also influenced by factors such as age, birth weight and central adiposity.
|
|
| 10. |
- Olsson, Anders H, et al.
(författare)
-
The expression of myosin heavy chain (MHC) genes in human skeletal muscle is related to metabolic characteristics involved in the pathogenesis of type 2 diabetes.
- 2011
-
Ingår i: Molecular Genetics and Metabolism. - : Elsevier BV. - 1096-7192. ; 103, s. 275-281
-
Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes patients exhibit a reduction in oxidative muscle fibres and an increase in glycolytic muscle fibres. In this study, we investigated whether both genetic and non-genetic factors influence the mRNA expression levels of three myosin heavy chain (MHC) genes represented in different fibre types. Specifically, we examined the MHC7 (slow-twitch oxidative fibre), MHCIIa (fast-twitch oxidative fibre) and MHCIIx/d (fast-twitch glycolytic fibre) genes in human skeletal muscle. We further investigated the use of MHC mRNA expression as a proxy to determine fibre-type composition, as measured by traditional ATP staining. Two cohorts of age-matched Swedish men were studied to determine the relationship of muscle mRNA expression of MHC7, MHCIIa, and MHCIIx/d with muscle fibre composition. A classical twin approach, including young and elderly Danish twin pairs, was utilised to examine if differences in expression levels were due to genetic or environmental factors. Although MHCIIx/d mRNA expression correlated positively with the level of type IIx/d muscle fibres in the two cohorts (P<0.05), a relatively low magnitude of correlation suggests that mRNA does not fully correlate with fibre-type composition. Heritability estimates and genetic analysis suggest that the levels of MHC7, MHCIIa and MHCIIx/d expression are primarily under non-genetic influence, and MHCIIa indicated an age-related decline. PGC-1α exhibited a positive relationship with the expression of all three MHC genes (P<0.05); meanwhile, PGC-1β related positively with MHCIIa expression and negatively with MHCIIx/d expression (P<0.05). While MHCIIa expression related positively with insulin-stimulated glucose uptake (P<0.01), MHCIIx/d expression related negatively with insulin-stimulated glucose uptake (P<0.05). Our findings suggest that the expression levels of the MHC genes are associated with age and both PGC-1α and PGC-1β and indicate that the MHC genes may to some extent be used to determine fibre-type composition in human skeletal muscle.
|
|
