scholarly journals Rosiglitazone-Mediated Effects on Skeletal Muscle Gene Expression Correlate with Improvements in Insulin Sensitivity in Individuals with HIV-Insulin Resistance

2011 ◽  
Vol 2011 ◽  
pp. 1-8
Author(s):  
Dennis C. Mynarcik ◽  
Margaret A. McNurlan ◽  
Mark M. Melendez ◽  
James A. Vosswinkel ◽  
Marie C. Gelato
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Tissue ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Gene Expression ◽  
Mediated Effects ◽  
Highly Correlated ◽  
Muscle Gene

Rosiglitazone, an agonist of peroxisome proliferator activated receptor (PPARγ), improves insulin sensitivity by increasing insulin-stimulated glucose uptake into muscle tissue. This study was undertaken to assess changes in expression of PPAR-regulated genes in muscle tissue following treatment of HIV-associated insulin resistance with rosiglitazone. Muscle gene expression was assessed in twenty-two seronegative HIV subjects (control), 21 HIV-infected individuals with normal insulin sensitivity (HIV-IS) and 19 HIV-infected individuals with insulin resistance (HIV-IR). A subset of the HIV-IR group (N=10) were re-evaluated 12 weeks after treatment with 8 mg/d of rosiglitazone. The HIV-IR group's rosiglitazone-mediated improvement in insulin sensitivity was highly correlated with increased expression of PPARγ and carnitine palmitoyl transferase-1 (CPT-1), (r=0.87, P<.001) and (r=0.95, P<.001), respectively. The changes in PPARγ expression were also correlated with the changes in CPT1 expression (r=0.75, P=.009). The results suggest that rosiglitazone; may have a direct effect on muscle tissue to improve insulin sensitivity.

scholarly journals Exercise training impacts skeletal muscle gene expression related to the kynurenine pathway

2019 ◽  
Vol 316 (3) ◽  
pp. C444-C448 ◽  
Author(s):  
David J. Allison ◽  
Joshua P. Nederveen ◽  
Tim Snijders ◽  
Kirsten E. Bell ◽  
Dinesh Kumbhare ◽  
...  
Keyword(s):  
Gene Expression ◽  
Older Adults ◽  
Skeletal Muscle ◽  
Transcription Factors ◽  
Exercise Training ◽  
Kynurenine Pathway ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Gene Expression ◽  
Muscle Gene

Exercise positively impacts mood and symptoms of depression; however, the mechanisms underlying these effects are not fully understood. Recent evidence highlights a potential role for skeletal muscle-derived transcription factors to influence tryptophan metabolism, along the kynurenine pathway, which has important implications in depression. This has important consequences for older adults, whose age-related muscle deterioration may influence this pathway and may increase their risk for depression. Although exercise training has been shown to improve skeletal muscle mass in older adults, whether this also translates into improvements in transcription factors and metabolites related to the kynurenine pathway has yet to be examined. The aim of the present study was to examine the influence of a 12-wk exercise program on skeletal muscle gene expression of transcription factors, kynurenine aminotransferase (KAT) gene expression, and plasma concentrations of tryptophan metabolites (kynurenines) in healthy older men over 65 yr of age. Exercise training significantly increased skeletal muscle gene expression of transcription factors (peroxisome proliferator-activated receptor-γ coactivator 1α, peroxisome proliferator-activated receptor-α, and peroxisome proliferator-activated receptor-δ: 1.77, 1.99, 2.18-fold increases, respectively, P < 0.01] and KAT isoforms 1–4 (6.5, 2.1, 2.2, and 2.6-fold increases, respectively, P ≤ 0.01). Concentrations of plasma kynurenines were not altered. These results demonstrate that 12 wk of exercise training significantly altered skeletal muscle gene expression of transcription factors and gene expression related to the kynurenine pathway, but not circulating kynurenine metabolites in older men. These findings warrant future research to determine whether distinct exercise modalities or varying intensities could induce a shift in the kynurenine pathway in depressed older adults.

scholarly journals Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽  
2020 ◽  
Vol 2020 ◽  
pp. 1-20
Author(s):  
Sakil Kulkarni ◽  
Jiansheng Huang ◽  
Eric Tycksen ◽  
Paul F. Cliften ◽  
David A. Rudnick
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Transcriptional Regulation ◽  
Mitochondrial Gene ◽  
Peroxisome Proliferator ◽  
Large Set ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

scholarly journals Skeletal muscle mitochondrial and metabolic responses to a high-fat diet in female rats bred for high and low aerobic capacity

2010 ◽  
Vol 35 (2) ◽  
pp. 151-162 ◽  
Author(s):  
Scott P. Naples ◽  
Sarah J. Borengasser ◽  
R. Scott. Rector ◽  
Grace M. Uptergrove ◽  
E. Matthew Morris ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
High Fat Diet ◽  
Female Rats ◽  
Mitochondrial Morphology ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Transcriptional Responses ◽  
Peroxisome Proliferator Activated Receptor

Rats selected artificially to be low-capacity runners (LCR) possess a metabolic syndrome phenotype that is worsened by a high-fat diet (HFD), whereas rats selected to be high-capacity runners (HCR) are protected against HFD-induced obesity and insulin resistance. This study examined whether protection against, or susceptibility to, HFD-induced insulin resistance in the HCR–LCR strains is associated with contrasting metabolic adaptations in skeletal muscle. HCR and LCR rats (generation 20; n = 5–6; maximum running distance ∼1800 m vs. ∼350 m, respectively (p < 0.0001)) were divided into HFD (71.6% energy from fat) or normal chow (NC) (16.7% energy from fat) groups for 7 weeks (from 24 to 31 weeks of age). Skeletal muscle (red gastrocnemius) mitochondrial-fatty acid oxidation (FAO), mitochondrial-enzyme activity, mitochondrial-morphology, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and peroxisome proliferator-activated receptor δ (PPARδ) expression and insulin sensitivity (intraperitoneal glucose tolerance tests) were measured. The HFD caused increased adiposity and reduced insulin sensitivity only in the LCR and not the HCR strain. Isolated mitochondria from the HCR skeletal muscle displayed a 2-fold-higher rate of FAO on NC, but both groups increased FAO following HFD. PGC-1α mRNA expression and superoxide dismutase activity were significantly reduced with the HFD in the LCR rats, but not in the HCR rats. PPARδ expression did not differ between strains or dietary conditions. These results do not provide a clear connection between protection of insulin sensitivity and HFD-induced adaptive changes in mitochondrial function or transcriptional responses but do not dismiss the possibility that elevated mitochondrial FAO in the HCR may play a protective role.

scholarly journals Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1αin Skeletal Muscle

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Fengxia Liang ◽  
Rui Chen ◽  
Atsushi Nakagawa ◽  
Makoto Nishizawa ◽  
Shinichi Tsuda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Fasting Blood Glucose ◽  
Low Frequency ◽  
Tolerance Test ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Obesity And Diabetes

Electroacupuncture (EA) has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1) and induced gene expression of peroxisome proliferator-activated receptor coactivator (PGC-), nuclear respiratory factor 1 (NRF1), and acyl-CoA oxidase (ACOX). These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-, thus resulting in improved insulin signal.

scholarly journals Nitrate and Nitrite Treatment Modulate Performance and Available Fuel Sources In Zebrafish Muscle and Liver

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1758-1758
Author(s):  
Rosa Keller ◽  
Laura Beaver ◽  
Patrick Reardon ◽  
Norman Hord
Keyword(s):  
Skeletal Muscle ◽  
Exercise Performance ◽  
Creatine Phosphate ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Muscle Gene Expression ◽  
Nitrate Treatment ◽  
Muscle Gene ◽  
Nitrate And Nitrite

Abstract Objectives Treatment with nitrate, but not nitrite, improves exercise performance but the mechanisms responsible are not fully understood. Thus, we tested the hypothesis that nitrate and nitrite treatment alter exercise performance through regulation of genes related to glucose and lipid metabolism in skeletal muscle and liver. Furthermore, we tested the hypothesis that nitrate treatment caused increased abundance and utilization of metabolic fuels in muscle that require less oxygen for energy production. Methods Adult zebrafish fish were exposed to sodium nitrate (606.9 mg NaNO3/L water), sodium nitrite (19.5 mg NaNO2/L of water), or control water for 21 days (n = 9–12/treatment). Liver and muscle gene expression were analyzed by quantitative real-time PCR and liver and muscle metabolomes were assessed by 1H-NMR untargeted metabolomics. Results Nitrite treatment significantly increased carnitine palmitoyl transferase 1b (cpt1b) expression in the liver and significantly decreased acetyl-CoA carboxylase (acaca) expression in skeletal muscle. Nitrate treatment significantly increased expression of peroxisome proliferator activated receptor-γ (pparg) muscle while acaca significantly decreased in skeletal muscle. Nitrate treatment also induced significant increases in metabolic fuels, such as ATP and creatine phosphate, and fuel sources including β-hydroxybutyrate and glycolytic intermediates in rested skeletal muscle. After a graded exercise test, these metabolites decreased in skeletal muscle of nitrate-treated fish while they increased with exercise in the skeletal muscle of control-treated zebrafish. Conclusions Our data are consistent with the hypothesis that nitrate treatment altered lipid and carbohydrate metabolism of zebrafish, in part, through a pparg mediated mechanism in the liver, and may improve exercise performance through utilization of fuel sources that require less oxygen during exercise. In contrast, our data indicate that nitrite may attenuate exercise performance, in part, by promoting dependence on fatty acid oxidation in the liver of zebrafish. These mechanisms may mediate improved exercise tolerance in populations with cardiovascular disease. Funding Sources Celia Strickland and G. Kenneth Austin III Endowment and National Institutes of Health.

scholarly journals The effects of obesity-associated insulin resistance on mRNA expression of peroxisome proliferator-activated receptor-γ target genes, in dogs

2007 ◽  
Vol 98 (3) ◽  
pp. 497-503 ◽  
Author(s):  
Constance Gayet ◽  
Veronique Leray ◽  
Masayuki Saito ◽  
Brigitte Siliart ◽  
Patrick Nguyen
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Mrna Expression ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Visceral Adipose

Visceral adipose tissue and skeletal muscle have central roles in determining whole-body insulin sensitivity. The peroxisome proliferator-activated receptor-γ (PPARγ) is a potential mediator of insulin sensitivity. It can directly modulate the expression of genes that are involved in glucose and lipid metabolism, including GLUT4, lipoprotein lipase (LPL) and adipocytokines (leptin and adiponectin). In this study, we aimed to determine the effects of obesity-associated insulin resistance on mRNA expression of PPARγ and its target genes. Dogs were studied when they were lean and at the end of an overfeeding period when they had reached a steady obese state. The use of a sensitive, real-time PCR assay allowed a relative quantification of mRNA expression for PPARγ, LPL, GLUT4, leptin and adiponectin, in adipose tissue and skeletal muscle. In visceral adipose tissue and/or skeletal muscle, mRNA expression of PPARγ, LPL and GLUT4 were at least 2-fold less in obese and insulin-resistant dogs compared with the same animals when they were lean and insulin-sensitive. The mRNA expression and plasma concentration of leptin was increased, whereas the plasma level and mRNA expression of adiponectin was decreased, by obesity. In adipose tissue, PPARγ expression was correlated with leptin and adiponectin. These findings, in an original model of obesity induced by a prolonged period of overfeeding, showed that insulin resistance is associated with a decrease in PPARγ mRNA expression that could dysregulate expression of several genes involved in glucose and lipid metabolism.

scholarly journals Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
De-Si Pan ◽  
Wei Wang ◽  
Nan-Song Liu ◽  
Qian-Jiao Yang ◽  
Kun Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism ◽  
Effective Part

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Temporal pattern of skeletal muscle gene expression following endurance exercise in Alaskan sled dogs

2009 ◽  
Vol 107 (2) ◽  
pp. 605-612 ◽  
Author(s):  
Eric P. Brass ◽  
Mette A. Peters ◽  
Kenneth W. Hinchcliff ◽  
Yudong D. He ◽  
Roger G. Ulrich
Keyword(s):  
Gene Expression ◽  
Endurance Exercise ◽  
Temporal Pattern ◽  
Regulatory Elements ◽  
Peroxisome Proliferator ◽  
Biceps Femoris Muscle ◽  
Muscle Gene Expression ◽  
Functional Relationships ◽  
Sled Dogs ◽  
Muscle Gene

Muscle responses to exercise are complex and include acute responses to exercise-induced injury, as well as longer term adaptive training responses. Using Alaskan sled dogs as an experimental model, changes in muscle gene expression were analyzed to test the hypotheses that important regulatory elements of the muscle's adaptation to exercise could be identified based on the temporal pattern of gene expression. Dogs were randomly assigned to undertake a 160-km run ( n = 9), or to remain at rest ( n = 4). Biceps femoris muscle was obtained from the unexercised dogs and two dogs at each of 2, 6, and 12 h after the exercise, and from three dogs 24 h after exercise. RNA was extracted and microarray analysis used to define gene transcriptional changes. The changes in gene expression after exercise occurred in a temporal pattern. Overall, 569, 469, 316, and 223 transcripts were differentially expressed at 2, 6, 12, and 24 h postexercise, respectively, compared with unexercised dogs (based on P ≤ 0.01 and an absolute fold change of ≥1.5). Increases in a number of known transcriptional regulators, including peroxisome proliferator-activated receptor-α, cAMP-responsive element modulator, and CCAAT enhancer binding protein-δ, and potential signaling molecules, including brain-derived neurotrophic factor, dermokine, and suprabasin, were observed 2 h after exercise. Biological functional analysis suggested changes in expression of genes with known functional relationships, including genes involved in muscle remodeling and growth, intermediary metabolism, and immune regulation. Sustained endurance exercise by Alaskan sled dogs induces coordinated changes in gene expression with a clear temporal pattern. RNA expression profiling has the potential to identify novel regulatory mechanisms and responses to exercise stimuli.

scholarly journals Transcription Suppression of Peroxisome Proliferator-Activated Receptor γ2 Gene Expression by Tumor Necrosis Factor α via an Inhibition of CCAAT/ Enhancer-binding Protein δ during the Early Stage of Adipocyte Differentiation

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 4948-4956 ◽  
Author(s):  
Masataka Kudo ◽  
Akira Sugawara ◽  
Akira Uruno ◽  
Kazuhisa Takeuchi ◽  
Sadayoshi Ito
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Gene Transcription ◽  
Adipocyte Differentiation ◽  
Early Stage ◽  
Binding Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Enhancer Binding Protein

Abstract TNFα is known to inhibit adipocyte differentiation and induce insulin resistance. Moreover, TNFα is known to down-regulate peroxisome proliferator-activated receptor (PPAR)γ2, an adipocyte-specific nuclear receptor of insulin-sensitizer thiazolidinediones. To clarify molecular mechanisms of TNFα- mediated PPARγ2 down-regulation, we here examined the effect of TNFα on transcription regulation of PPARγ2 gene expression during the early stage of adipocyte differentiation. 3T3-L1 preadipocytes (2 d after 100% confluent) were incubated in a differentiation mixture (dexamethasone, insulin, 3-isobutyl-1-methlxanthine), with or without 50 ng/ml TNFα, for 24 h. TNFα significantly decreased PPARγ2 expression both at mRNA and protein levels (to ∼40%), as well as aP2 mRNA expression. The mouse PPARγ2 gene promoter region (2.2-kb) was isolated and was used for luciferase reporter assays by transient transfection. TNFα significantly suppressed PPARγ2 gene transcription (to ∼50%), and deletion analyses demonstrated that the suppression was mediated via CCAAT/enhancer-binding protein (C/EBP) binding elements at the −320/−340 region of the promoter. Moreover, TNFα significantly decreased expression of C/EBPδ mRNA and protein levels (to ∼40%). EMSA, using 3T3-L1 cells nuclear extracts with the −320/−340 region as a probe, demonstrated the binding of C/EBPδ to the element, which was significantly decreased by TNFα treatment. Overexpression of CEBP/δ prevented the TNFα-mediated suppression of PPARγ2 transactivation. Taken together, TNFα suppresses PPARγ2 gene transcription by the inhibition of C/EBPδ expression and its DNA binding during the early stage of adipocyte differentiation, which may contribute to the inhibition of adipocyte differentiation, as well as the induction of insulin resistance.

scholarly journals Deoxyribonucleic Acid Methylation and Gene Expression of PPARGC1A in Human Muscle Is Influenced by High-Fat Overfeeding in a Birth-Weight-Dependent Manner

2010 ◽  
Vol 95 (6) ◽  
pp. 3048-3056 ◽  
Author(s):  
Charlotte Brøns ◽  
Stine Jacobsen ◽  
Emma Nilsson ◽  
Tina Rönn ◽  
Christine B. Jensen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Dna Methylation ◽  
Birth Weight ◽  
Control Diet ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peripheral Insulin Resistance

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 γ, coactivator 1α (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 &lt; 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.

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