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 < 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.

scholarly journals Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: role of apoptosis, adiponectin and tumour necrosis factor-α

2007 ◽  
Vol 97 (2) ◽  
pp. 389-398 ◽  
Author(s):  
Patricia Pérez-Matute ◽  
Nerea Pérez-Echarri ◽  
J. Alfredo Martínez ◽  
Amelia Marti ◽  
María J. Moreno-Aliaga
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Control Diet ◽  
Cafeteria Diet ◽  
High Fat ◽  
Beneficial Effects

n-3 PUFA have shown potential anti-obesity and insulin-sensitising properties. However, the mechanisms involved are not clearly established. The aim of the present study was to assess the effects of EPA administration, one of the n-3 PUFA, on body-weight gain and adiposity in rats fed on a standard or a high-fat (cafeteria) diet. The actions on white adipose tissue lipolysis, apoptosis and on several genes related to obesity and insulin resistance were also studied. Control and cafeteria-induced overweight male Wistar rats were assigned into two subgroups, one of them daily received EPA ethyl ester (1 g/kg) for 5 weeks by oral administration. The high-fat diet induced a very significant increase in both body weight and fat mass. Rats fed with the cafeteria diet and orally treated with EPA showed a marginally lower body-weight gain (P = 0·09), a decrease in food intake (P < 0·01) and an increase in leptin production (P < 0·05). EPA administration reduced retroperitoneal adipose tissue weight (P < 0·05) which could be secondary to the inhibition of the adipogenic transcription factor PPARγ gene expression (P < 0·001), and also to the increase in apoptosis (P < 0·05) found in rats fed with a control diet. TNFα gene expression was significantly increased (P < 0·05) by the cafeteria diet, while EPA treatment was able to prevent (P < 0·01) the rise in this inflammatory cytokine. Adiposity-corrected adiponectin plasma levels were increased by EPA. These actions on both TNFα and adiponectin could explain the beneficial effects of EPA on insulin resistance induced by the cafeteria diet.

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 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.

scholarly journals Synbiotic kefir lowered peroxisome proliferator activated receptor gamma (PPARγ) gene expression in rat fed high-fat and high-fructose diet

2020 ◽  
Author(s):  
Nurliyani ◽  
Eni Harmayani ◽  
Sunarti
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Blood Glucose ◽  
Peroxisome Proliferator ◽  
Milk Product ◽  
High Fat ◽  
Necrosis Factor Alpha ◽  
Peroxisome Proliferator Activated Receptor ◽  
High Fructose Diet ◽  
High Fructose

Abstract Kefir is fermented milk product containing bacteria and yeast, whereas glucomannan from porang (Amorphophallus oncophyllus) tuber has known as prebiotic in vivo. Diets with a high fat and high sugar will stimulate metabolic syndrome. The objective of this study were to determine the effect of synbiotic kefir (goat milk kefir enriched with porang glucomannan) on blood glucose, hemoglobin A1c (HbA1c), free fatty acid (FFA), tumor necrosis factor alpha (TNF-α), gene expression of peroxisome proliferator activated receptor gamma (PPARγ), and insulin producing cells in rat fed high- fat and high- fructose (HFHF) diet. Rats were divided into 5 groups: normal; high fat high fructose (HFHF); HFHF + probiotic kefir; HFHF + synbiotic kefir; and HFHF + simvastatin. There was no significantly differences in plasma blood glucose in HFHF rat after treated with synbiotic kefir. However, synbiotic kefir could decrease HbA1c and plasma TNFα, and inhibit the increasing FFA in HFHF rats. Probiotic and synbiotic kefir could decrease gene expression of PPARγ2 in both of adipose and liver tissue in HFHF rats, but had no effect on total number of Langerhans islet and insulin producing cell. In conclusion, synbiotic kefir could ameliorate the health of rats in condition of high-fat and high-fructose diet, through decreasing in HbA1c, TNFα, and gene expression of PPARγ2 and also prevent the increasing of FFA. Therefore, synbiotic kefir containing porang glucomannan is expected to be a suggestion for the food industry to develop synbiotic-based functional foods which has the potential to improve metabolic syndrome

scholarly journals Hepatic Cerebroside Sulfotransferase Is Induced by PPARα Activation in Mice

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Takefumi Kimura ◽  
Takero Nakajima ◽  
Yuji Kamijo ◽  
Naoki Tanaka ◽  
Lixuan Wang ◽  
...  
Keyword(s):  
Target Genes ◽  
Control Diet ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolism Enzymes ◽  
Key Enzyme

Sulfatides are one of the major sphingoglycolipids in mammalian serum and are synthesized and secreted mainly from the liver as a component of lipoproteins. Recent studies revealed a protective role for serum sulfatides against arteriosclerosis and hypercoagulation. Although peroxisome proliferator-activated receptor (PPAR)αhas important functions in hepatic lipoprotein metabolism, its association with sulfatides has not been investigated. In this study, sulfatide levels and the expression of enzymes related to sulfatide metabolism were examined using wild-type (+/+),Ppara-heterozygous (+/−), andPpara-null (−/−) mice given a control diet or one containing 0.1% fenofibrate, a clinically used hypolipidemic drug and PPARαactivator. Fenofibrate treatment increased serum and hepatic sulfatides inPpara(+/+) and (+/−) mice through a marked induction of hepatic cerebroside sulfotransferase (CST), a key enzyme in sulfatide synthesis, in a PPARα-dependent manner. Furthermore, increases in CST mRNA levels were correlated with mRNA elevations of several known PPARαtarget genes, and such changes were not observed for other sulfatide-metabolism enzymes in the liver. These results suggest that PPARαactivation enhances hepatic sulfatide synthesis via CST induction and implicate CST as a novel PPARαtarget gene.

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.

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