Expression of the peroxisome proliferator activated receptor gamma gene is repressed by DNA methylation in visceral adipose tissue of mouse models of diabetes

Foxp3+CD4+ regulatory T cells (Tregs) regulate most types of immune response as well as several processes important for tissue homeostasis, for example, metabolism and repair. Dedicated Treg compartments—with distinct transcriptomes, T cell receptor repertoires, and growth/survival factor dependencies—have been identified in several nonlymphoid tissues. These Tregs are specifically adapted to function and operate in their home tissue—When, where, and how do they take on their specialized characteristics? We recently reported that a splenic Treg population expressing low levels of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) contains precursors of Tregs residing in visceral adipose tissue. This finding made sense given that PPARγ, the “master regulator” of adipocyte differentiation, is required for the accumulation and function of Tregs in visceral adipose tissue but not in lymphoid tissues. Here we use single-cell RNA sequencing, single-cell Tcra and Tcrb sequencing, and adoptive-transfer experiments to show that, unexpectedly, the splenic PPARγlo Treg population is transcriptionally heterogeneous and engenders Tregs in multiple nonlymphoid tissues beyond visceral adipose tissue, such as skin and liver. The existence of a general pool of splenic precursors for nonlymphoid-tissue Tregs opens possibilities for regulating their emergence experimentally or therapeutically.

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Effect of Eight Weeks of Aerobic Progressive Training with Capsaicin on Changes in PGC-1α and UPC-1 Expression in Visceral Adipose Tissue of Obese Rats With Diet

Complementary Medicine Journal ◽

10.32598/cmja.10.2.627.4 ◽

2020 ◽

Vol 10 (2) ◽

pp. 106-117

Author(s):

Maryam Mostafavian ◽

◽

Ahmad Abdi ◽

Javad Mehrabani ◽

Alireza Barari ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Uncoupling Protein ◽

Normal Diet ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Visceral Adipose

Objective: Decreased physical activity coupled with increased High‐Fat Diet (HFD) intake prompts obesity. Current research suggests that changing White Adipose Tissue (WAT) to brown promotes energy expenditure to counter obesity. The purpose of this study was to investigate the effects of aerobic Progressive training and Capsaicin (Cap) on Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and Uncoupling protein-1 (UPC-1) gene expression in rat fed a high-fat diet. Methods: 40 male Wistar rats aged 8-12 weeks, were fed a Normal Diet (ND) (n=8) or HFD (n=32) for 8 weeks. After 8 weeks, rats were divided into 5 groups: ND, HFD, High-Fat Diet-Training (HFDT), High-Fat Diet-Capsaicin (HFDCap), high-fat diet-training-capsaicin (HFDTCap). Training groups have performed a progressive aerobic running program on a motor-driven treadmill for eight weeks. Capsaicin (4 mg/kg/day) were administered orally, by gavage, once a day. PGC-1α and UCP-1 gene expression levels in the VAT were measured by Real-time PCR method. Results: The results of this study showed that PGC-1α and UCP-expression was decreased in HFD group compared to ND group. Also, the expression of PGC-1α and UPC-1 in HFDT, HFDCap and HFDTCap groups was significantly increased compared to HFD. The expression of PGC-1α and UPC-1 in HFDTCap was also significantly increased compared to HFDT and HFDCap groups. Conclusion: Possibly, eight weeks of progressive training combined with capsaicin administration has an effect on the browning of visceral adipose tissue in HFD rats by increasing expression of PGC-1α and UCP-1.

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The Expression/Methylation Profile of Adipogenic and Inflammatory Transcription Factors in Adipose Tissue Are Linked to Obesity-Related Colorectal Cancer

Cancers ◽

10.3390/cancers11111629 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1629 ◽

Cited By ~ 4

Author(s):

Hatim Boughanem ◽

Amanda Cabrera-Mulero ◽

Pablo Hernández-Alonso ◽

Borja Bandera-Merchán ◽

Alberto Tinahones ◽

...

Keyword(s):

Colorectal Cancer ◽

Adipose Tissue ◽

Transcription Factors ◽

Visceral Adipose Tissue ◽

Critical Role ◽

Colorectal Carcinogenesis ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Obese Control ◽

Visceral Adipose

Obesity is well accepted as crucial risk factor that plays a critical role in the initiation and progression of colorectal cancer (CRC). More specifically, visceral adipose tissue (VAT) in people with obesity could produce chronic inflammation and an altered profile expression of key transcription factors that promote a favorable microenvironment to colorectal carcinogenesis. For this, the aim of this study was to explore the relationship between adipogenic and inflammatory transcription factors in VAT from nonobese, obese, and/or CRC patients. To test this idea, we studied the expression and methylation of CCAAT-enhancer binding protein type alpha (C/EBP-α), peroxisome proliferator-activated receptor gamma (PPAR-γ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) in VAT from non-obese control, non-obese CRC subjects, overweight/obese control, and overweight/obese CRC patients and their correlation with anthropometric and biochemical variables. We found decreased expression of C/EBP-α in overweight/obese CRC patients in comparison with overweight/obese control subjects. PGC-1α and NF-κB were overexpressed in CRC patients independently of the BMI. NF-κB promoter was hypomethylated in overweight/obese CRC patients when compared to overweight/obese control individuals. In addition, multiple significant correlations between expression, methylation, and biochemical parameters were found. Finally, linear regression analysis showed that the expression of C/EBP-α and NF-κB and that NF-κB methylation were associated with CRC and able to explain up to 55% of CRC variability. Our results suggest that visceral adipose tissue may be a key factor in tumor development and inflammatory state. We propose C/EBP-α, PGC-1α and NF-κB to be interesting candidates as potential biomarkers in adipose tissue for CRC patients.

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24 The effect of bariatric surgery on DNA methylation in blood and omental visceral adipose tissue

10.1055/s-0041-1735683 ◽

2021 ◽

Author(s):

Luise Müller ◽

Lena Gras ◽

Anne Hoffmann ◽

Tobias Hagemann ◽

Stephan H. Bernhart ◽

...

Keyword(s):

Bariatric Surgery ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Visceral Adipose

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Epigenetic Downregulation of FASN in Visceral Adipose Tissue of Insulin Resistant Subjects

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1150-7446 ◽

2020 ◽

Author(s):

Helen Sievert ◽

Christin Krause ◽

Cathleen Geißler ◽

Martina Grohs ◽

Alexander T. El-Gammal ◽

...

Keyword(s):

Type 2 Diabetes ◽

Dna Methylation ◽

Fatty Acids ◽

Adipose Tissue ◽

Glucose Intolerance ◽

Visceral Adipose Tissue ◽

High Hba1c ◽

Obese Subjects ◽

Visceral Adipose

Abstract Objective The risk to develop type 2 diabetes increases with the amount of visceral adiposity presumably due to increased lipolysis and subsequent lipid accumulation in visceral organs. However, data describing the molecular regulation of these pathways in humans are rare. We tested if genes of the lipogenic and lipolytic pathways are associated with glucose intolerance independently of obesity in visceral adipose tissue (VAT) of obese subjects. Moreover, we studied DNA methylation of FASN (fatty acid synthase), that catalyses the synthesis of long-chain fatty acids, in VAT of the same subjects and whether it is associated with metabolic traits. Subjects and methods Visceral adipose tissue biopsies and blood samples were taken from 93 severely obese subjects undergoing bariatric surgery. Subjects were grouped in low HbA1c (L-HbA1c, HbA1c<6.5 %) and high HbA1c (H-HbA1c, HbA1c≥6.5 %) groups and expression of genes from the lipogenic and lipolytic pathways was analysed by TaqMan qPCR. DNA methylation of FASN was quantified by bisulfite-pyrosequencing. Results FASN expression was downregulated in visceral fat from subjects with high HbA1c (p = 0.00009). Expression of other lipogenetic (SCD, ELOVL6) or lipolytic genes (ADRB3, PNPLA2) and FABP4 was not changed. DNA methylation of FASN was increased at a regulatory ChoRE recognition site in the H-HbA1c-subgroup and correlated negatively with FASN mRNA (r = − 0.302, p = 0.0034) and positively with HbA1c (r = 0.296, p = 0.0040) and blood glucose (r = 0.363, p = 0.0005). Conclusions Epigenetic downregulation of FASN in visceral adipose tissue of obese subjects might contribute to limited de novo lipogenesis of important insulin sensitizing fatty acids and could thereby contribute to glucose intolerance and the development of type 2 diabetes independently of obesity.

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Comparison of visceral adipose tissue DNA methylation and gene expression profiles in female adolescents with obesity

10.1101/728832 ◽

2019 ◽

Author(s):

Matthew D. Barberio ◽

Evan P. Nadler ◽

Samantha Sevilla ◽

Rosemary Lu ◽

Brennan Harmon ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Akt Signaling ◽

Adolescent Females ◽

Akt Signaling Pathway ◽

Visceral Adipose

AbstractBackgroundEpigenetic changes in visceral adipose tissue (VAT) with obesity and their effects on gene expression are poorly understood, especially during emergent obesity in youth. The current study tested the hypothesis that methylation and gene expression profiles of key growth factor and inflammatory pathways such as PI3K/AKT signaling are altered in VAT from obese compared to non-obese youth.MethodsVAT samples from adolescent females grouped as Lean (L; n=15; age=15±3 yrs, BMI=21.9±3.0 kg/m2) or Obese (Ob; n=15, age=16±2 yrs, BMI=45.8±9.8 kg/m2) were collected. Global methylation (n=20) and gene expression (N=30) patterns were profiled via microarray and interrogated for differences between groups by ANCOVA (p<0.05), followed by biological pathway analysis.ResultsOverlapping differences in methylation and gene expression in 317 genes were found in VAT from obese compared to lean groups. PI3K/AKT Signaling (p=1.83×10−6; 10/121 molecules in dataset/pathway) was significantly overrepresented in Ob VAT according to pathway analysis. mRNA upregulations in the PI3K/AKT Signaling Pathway genes TFAM (p=0.03; Fold change=1.8) and PPP2R5C (p=0.03, FC=2.6) were confirmed via qRT-PCR.ConclusionOur analyses show obesity-related differences in DNA methylation and gene expression in visceral adipose tissue of adolescent females. Specifically, we identified methylation site/gene expression pairs differentially regulated and mapped these differences to PI3K/AKT signaling, suggesting that PI3K/AKT signaling pathway dysfunction in obesity may be driven in part by obesity-related changes in DNA methylation.

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Association between serum 25-hydroxyvitamin D and global DNA methylation in visceral adipose tissue from colorectal cancer patients

BMC Cancer ◽

10.1186/s12885-018-5226-4 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 8

Author(s):

Daniel Castellano-Castillo ◽

Sonsoles Morcillo ◽

Ana B. Crujeiras ◽

Lidia Sánchez-Alcoholado ◽

Mercedes Clemente-Postigo ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Adipose Tissue ◽

Cancer Patients ◽

Visceral Adipose Tissue ◽

Global Dna Methylation ◽

Hydroxyvitamin D ◽

25 Hydroxyvitamin D ◽

Colorectal Cancer Patients ◽

Visceral Adipose

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Comparison of visceral adipose tissue DNA methylation and gene expression profiles in female adolescents with obesity

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-019-0494-y ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 5

Author(s):

Matthew D. Barberio ◽

Evan P. Nadler ◽

Samantha Sevilla ◽

Rosemary Lu ◽

Brennan Harmon ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Akt Signaling ◽

Adolescent Females ◽

Akt Signaling Pathway ◽

Visceral Adipose

Abstract Background Epigenetic changes in visceral adipose tissue (VAT) with obesity and their effects on gene expression are poorly understood, especially during emergent obesity in youth. The current study tested the hypothesis that methylation and gene expression profiles of key growth factor and inflammatory pathways are altered in VAT from obese compared to non-obese youth. Methods VAT samples from adolescent females grouped as Lean (L; n = 15; age = 15 ± 3 years, BMI = 21.9 ± 3.0 kg/m2) or Obese (Ob; n = 15, age = 16 ± 2 years, BMI = 45.8 ± 9.8 kg/m2) were collected. Global methylation (n = 20) and gene expression (N = 30) patterns were profiled via microarray and interrogated for differences between groups by ANCOVA (p < 0.05), followed by biological pathway analyses. Results Overlapping differences in methylation and gene expression in 317 genes were found in VAT from obese compared to lean groups. PI3K/AKT Signaling (p = 1.83 × 10−6; 11/121 molecules in dataset/pathway) was significantly overrepresented in Ob VAT according to pathway analysis. Upregulations in the PI3K/AKT signaling pathway mRNAs TFAM (p = 0.03; fold change = 1.8) and PPP2R5C (p = 0.03, FC = 2.6) were confirmed via qRT-PCR. Conclusion Our analyses show obesity-related differences in DNA methylation and gene expression in visceral adipose tissue of adolescent females. Specifically, we identified methylation site/gene expression pairs differentially regulated and mapped these differences to pathways including PI3K/AKT signaling, suggesting that PI3K/AKT signaling pathway dysfunction in obesity may be driven in part by changes in DNA methylation.

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

British Journal Of Nutrition ◽

10.1017/s000711450772514x ◽

2007 ◽

Vol 98 (3) ◽

pp. 497-503 ◽

Cited By ~ 33

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.

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