Exercise-associated generation of PPARγ ligands activates PPARγ signaling events and upregulates genes related to lipid metabolism

2012 ◽  
Vol 112 (5) ◽  
pp. 806-815 ◽  
Author(s):  
A. W. Thomas ◽  
N. A. Davies ◽  
H. Moir ◽  
L. Watkeys ◽  
J. S. Ruffino ◽  
...  
Keyword(s):  
Training Program ◽  
Target Genes ◽  
Exercise Program ◽  
Exercise Bout ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Exercise Induced

The aim of the present study was to test the hypotheses that exercise is associated with generation of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in the plasma and that this may activate PPARγ signaling within circulating monocytes, thus providing a mechanism to underpin the exercise-induced antiatherogenic benefits observed in previous studies. A cohort of healthy individuals undertook an 8-wk exercise-training program; samples were obtained before (Pre) and after (Post) standardized submaximal exercise bouts (45 min of cycling at 70% of maximal O2 uptake, determined at baseline) at weeks 0, 4, and 8. Addition of plasma samples to PPARγ response element (PPRE)-luciferase reporter gene assays showed increased PPARγ activity following standardized exercise bouts (Post/Pre = 1.23 ± 0.10 at week 0, P < 0.05), suggesting that PPARγ ligands were generated during exercise. However, increases in PPARγ/PPRE-luciferase activity in response to the same standardized exercise bout were blunted during the training program (Post/Pre = 1.18 ± 0.14 and 1.10 ± 0.10 at weeks 4 and 8, respectively, P > 0.05 for both), suggesting that the relative intensity of the exercise may affect PPARγ ligand generation. In untrained individuals, specific transient increases in monocyte expression of PPARγ-regulated genes were observed within 1.5–3 h of exercise (1.7 ± 0.4, 2.6 ± 0.4, and 1.4 ± 0.1 fold for CD36, liver X receptor-α, and ATP-binding cassette subfamily A member 1, respectively, P < 0.05), with expression returning to basal levels within 24 h. In contrast, by the end of the exercise program, expression at the protein level of PPARγ target genes had undergone sustained increases that were not associated with an individual exercise bout (e.g., week 8 Pre/ week 0 Pre = 2.79 ± 0.61 for CD36, P < 0.05). Exercise is known to upregulate PPARγ-controlled genes to induce beneficial effects in skeletal muscle (e.g., mitochondrial biogenesis and aerobic respiration). We suggest that parallel exercise-induced benefits may occur in monocytes, as monocyte PPARγ activation has been linked to beneficial antidiabetic effects (e.g., exercise-induced upregulation of monocytic PPARγ-controlled genes is associated with reverse cholesterol transport and anti-inflammatory effects). Thus, exercise-triggered monocyte PPARγ activation may constitute an additional rationale for prescribing exercise to type 2 diabetes patients.

scholarly journals From Exercise to Cognitive Performance: Role of Irisin

2021 ◽  
Vol 11 (15) ◽  
pp. 7120
Author(s):  
Mirko Pesce ◽  
Irene La Fratta ◽  
Teresa Paolucci ◽  
Alfredo Grilli ◽  
Antonia Patruno ◽  
...  
Keyword(s):  
The Elderly ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
General Exercise ◽  
Fibronectin Type Iii ◽  
Exercise Induced ◽  
Fibronectin Type Iii Domain ◽  
The Brain

The beneficial effects of exercise on the brain are well known. In general, exercise offers an effective way to improve cognitive function in all ages, particularly in the elderly, who are considered the most vulnerable to neurodegenerative disorders. In this regard, myokines, hormones secreted by muscle in response to exercise, have recently gained attention as beneficial mediators. Irisin is a novel exercise-induced myokine, that modulates several bodily processes, such as glucose homeostasis, and reduces systemic inflammation. Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5), a transmembrane precursor protein expressed in muscle under the control of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). The FNDC5/irisin system is also expressed in the hippocampus, where it stimulates the expression of the neurotrophin brain-derived neurotrophic factor in this area that is associated with learning and memory. In this review, we aimed to discuss the role of irisin as a key mediator of the beneficial effects of exercise on synaptic plasticity and memory in the elderly, suggesting its roles within the main promoters of the beneficial effects of exercise on the brain.

scholarly journals Cyclin G2 Regulates Adipogenesis through PPARγ Coactivation

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5247-5254 ◽  
Author(s):  
Victor Aguilar ◽  
Jean-Sébastien Annicotte ◽  
Xavier Escote ◽  
Joan Vendrell ◽  
Dominique Langin ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cell Cycle Regulators ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclin G2 ◽  
Regulatory Effects

Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.

Tumor necrosis factor-α inhibits peroxisome proliferator-activated receptor γ activity at a posttranslational level in hepatic stellate cells

2004 ◽  
Vol 286 (5) ◽  
pp. G722-G729 ◽  
Author(s):  
Chin K. Sung ◽  
Hongyun She ◽  
Shigang Xiong ◽  
Hidekazu Tsukamoto
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Critical Event ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

Diminished activity of peroxisome proliferator-activated receptor γ (PPARγ) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARγ regulation by TNF-α in an HSC line designated as BSC. In BSC, TNF-α decreased both basal and ligand (GW1929)-induced PPARγ mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-α showed decreased binding of PPARγ to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARγ1 expression vector and a PPRE-luciferase reporter gene, TNF-α decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-α increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser82 of PPARγ1 and resultant negative regulation of PPARγ transactivity. In fact, TNF-α failed to inhibit transactivity of a Ser82Ala PPARγ1 mutant in BSC. TNF-α-mediated inhibition of PPARγ transactivity was not blocked with a Ser32Ala/Ser36Ala mutant of inhibitory NF-κBα (IκBα). These results suggest that TNF-α inhibits PPARγ transactivity in cultured HSC, at least in part, by diminished PPARγ-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser82 of PPARγ1, but not via the NF-κB pathway.

scholarly journals Molecular basis of non-responsiveness to peroxisome proliferators: the guinea-pig PPARα is functional and mediates peroxisome proliferator-induced hypolipidaemia

1998 ◽  
Vol 332 (3) ◽  
pp. 689-693 ◽  
Author(s):  
Alex R. BELL ◽  
Richard SAVORY ◽  
Neill J. HORLEY ◽  
Agharul I. CHOUDHURY ◽  
Maurice DICKINS ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Molecular Basis ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferators ◽  
Luciferase Reporter Gene ◽  
Pig Liver ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Response Element ◽  
Guinea Pig Liver

The guinea pig does not undergo peroxisome proliferation in response to peroxisome proliferators, in contrast with other rodents. To understand the molecular basis of this phenotype, the peroxisome proliferator activated receptor α (PPARα) from guinea-pig liver was cloned; it encodes a protein of 467 amino acid residues that is similar to rodent and human PPARα. The guinea-pig PPARα showed a high substitution rate: maximum likelihood analysis was consistent with rodent monophyly, but could not exclude rodent polyphyly (P≈ 0.06). The guinea-pig PPARα cDNA was expressed in 293 cells and mediated the induction of the luciferase reporter gene by the peroxisome proliferator, Wy-14,643, dependent on the presence of a peroxisome proliferator response element. Moreover the PPARα RNA and protein were expressed in guinea-pig liver, although at lower levels than in a species which is responsive to peroxisome proliferators, the mouse. To determine whether the guinea-pig PPARα mediated any physiological effects, guinea pigs were exposed to two selective PPARα agonists, Wy-14,643 and methylclofenapate; both compounds induced hypolipidaemia. Thus the guinea pig is a useful model for human responses to peroxisome proliferators.

scholarly journals A systematic upregulation of nuclear and mitochondrial genes is not present in the initial postexercise recovery period in human skeletal muscle

2017 ◽  
Vol 42 (6) ◽  
pp. 571-578 ◽  
Author(s):  
Trisha D. Scribbans ◽  
Brittany A. Edgett ◽  
Jacob T. Bonafiglia ◽  
Brittany L. Baechler ◽  
Joe Quadrilatero ◽  
...  
Keyword(s):  
Oxygen Uptake ◽  
Messenger Rna ◽  
Acute Exercise ◽  
Recovery Period ◽  
Exercise Bout ◽  
Peak Oxygen Uptake ◽  
Peroxisome Proliferator ◽  
Glycogen Depletion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Exercise Induced

The purpose of the current investigation was to determine if an exercise-mediated upregulation of nuclear and mitochondrial-encoded genes targeted by the transcriptional co-activator peroxisome-proliferator-activated receptor gamma co-activator-1 alpha (PGC-1α) occurs in a systematic manner following different exercise intensities in humans. Ten recreationally active males (age: 23 ± 3 years; peak oxygen uptake: 41.8 ± 6.6 mL·kg−1·min−1) completed 2 acute bouts of work-matched interval exercise at ∼73% (low; LO) and ∼100% (high; HI) of work rate at peak oxygen uptake in a randomized crossover design. Muscle biopsies were taken before, immediately after, and 3 h into recovery following each exercise bout. A main effect of time (p < 0.05) was observed for glycogen depletion. PGC-1α messenger RNA (mRNA) increased following both conditions and was significantly (p < 0.05) higher following HI compared with LO (PGC-1α, LO: +442% vs. HI: +845%). PDK4 mRNA increased following LO whereas PPARα, NRF1, and CS increased following HI. However, a systematic upregulation of nuclear and mitochondrial-encoded genes was not present as TFAM, COXIV, COXI, COXII, ND1, and ND4 mRNA were unchanged. However, changes in COXI, COXII, ND1 and ND4 mRNA were positively correlated following LO and COXI, ND1, and ND4 were positively correlated following HI, which suggests mitochondrial-encoded gene expression was coordinated. PGC-1α and ND4 mRNA, as well as PGC-1α mRNA and the change in muscle glycogen, were positively correlated in response to LO. The lack of observed systematic upregulation of nuclear- and mitochondrial-encoded genes suggests that exercise-induced upregulation of PGC-1α targets are differentially regulated during the initial hours following acute exercise in humans.

scholarly journals Potentiation of TNF-α–Stimulated Group IIA Phospholipase A2 Expression by Peroxisome Proliferator–Activated Receptor α Activators in Rat Mesangial Cells

2002 ◽  
Vol 13 (3) ◽  
pp. 611-620 ◽  
Author(s):  
Kirsten Scholz-Pedretti ◽  
Annette Gans ◽  
Karl-Friedrich Beck ◽  
Josef Pfeilschifter ◽  
Marietta Kaszkin
Keyword(s):  
Promoter Activity ◽  
Mesangial Cells ◽  
Site Directed Mutagenesis ◽  
Lipid Lowering ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Glomerular Mesangial Cells ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

ABSTRACT. Natural activators of peroxisome proliferator–activated receptors (PPAR) are lipid metabolites, including those produced by phospholipases A2 (PLA2). In glomerular mesangial cells, the secreted group IIA PLA2 (sPLA2-IIA), which is thought to be a crucial factor in pathologic processes in the kidney, may provide free fatty acids and eicosanoids directly or indirectly, by activating a cytosolic PLA2. The scope of this study was to investigate whether synthetic PPARα activators have an effect on sPLA2-IIA mRNA expression in rat mesangial cells, thus constituting a feedback modulation of sPLA2-IIA transcription. In the presence of tumor necrosis factor–α (TNF-α), the PPARα agonists WY14643 and LY171883 as well as the lipid-lowering compound clofibrate potentiated expression, secretion, and activity of group IIA sPLA2 in mesangial cells. MK886, known as a noncompetitive inhibitor of PPARα, completely abolished the potentiation of sPLA2-IIA secretion and activity by WY14643, thus indicating that the effect of WY14643 is specifically mediated by PPARα. When cells were transfected with different constructs of the rat sPLA2-IIA promoter fused to a luciferase reporter gene, a stimulation with TNF-α in the presence of the PPARα activators caused an enhanced promoter activity compared with that induced by TNF-α alone. Site-directed mutagenesis of a putative PPRE site in the sPLA2-IIA promoter abolished the potentiating effect of PPARα agonists, thus strongly indicating its contribution to the enhanced promoter activity. In summary, this study shows that the rat sPLA2-IIA promoter is sensitive to PPARα agonists, which act synergistically with cytokines, resulting in an enhanced expression of sPLA2-IIA in rat mesangial cells.

scholarly journals MicroRNA Sequencing Reveals the Effect of Different Levels of Non-Fibrous Carbohydrate/Neutral Detergent Fiber on Rumen Development in Calves

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 496
Author(s):  
Mingming Xue ◽  
Kejun Wang ◽  
Ansi Wang ◽  
Ruiting Li ◽  
Yadong Wang ◽  
...  
Keyword(s):  
Target Genes ◽  
Neutral Detergent Fiber ◽  
Statistical Testing ◽  
Functional Enrichment ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Mixed Diet ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rumen Development

Rumen development in calves is affected by many factors, including dietary composition. MicroRNAs (miRNAs) are known to function in the development of the rumen in cattle, what is not known is how these miRNAs function in rumen development of calves fed with high and low ratios of non-fibrous carbohydrate (NFC)/neutral detergent fiber (NDF). A total of six healthy Charolais hybrids bull calves of similar weight were divided into two groups; three calves were fed a mixed diet with NFC/NDF = 1.35 (H group), and three were fed a mixed diet with NFC/NDF = 0.80 (L group). After 105 days on the diet, calves were sacrificed and rumen tissues were collected. Tissues were subjected to histological observation and miRNA expression analysis. Functional enrichment analysis was conducted on the target genes of the miRNAs. Targeting and regulatory relationships were verified by luciferase reporter assay and quantitative PCR (qPCR). We found that the length of rumen papilla in the L group was significantly greater than that in the H group, while the width of rumen papilla in H group was significantly greater than that that in L group. We identified 896 miRNAs; 540 known miRNAs, and 356 novel predicted miRNAs. After statistical testing, we identified 24 differentially expressed miRNAs (DEmiRNAs). miRNA-mRNA-cluster network analysis and literature reviews revealed that cell proliferation, differentiation, physical and nutrient stimuli processes participate in rumen development under different NFC/NDF levels. The regulatory relationships between three DEmiRNAs and five target genes were verified by examining the levels of expression. The binding sites on bta-miR-128 for the peroxisome proliferator activated receptor gamma (PPARG) and solute carrier family 16 member 1 (SLC16A1) genes were investigated using a dual luciferase assay. The results of this study provide insight into the role of miRNAs in rumen development in calves under different NFC/NDF levels.

scholarly journals The Herbal DrugMelampyrum pratenseL. (Koch): Isolation and Identification of Its Bioactive Compounds Targeting Mediators of Inflammation

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
S. Vogl ◽  
A. G. Atanasov ◽  
M. Binder ◽  
M. Bulusu ◽  
M. Zehl ◽  
...  
Keyword(s):  
Target Genes ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Luciferase Reporter Gene ◽  
Isolation And Identification ◽  
Protein Levels ◽  
Proinflammatory Mediators ◽  
Mediators Of Inflammation ◽  
Anti Inflammatory

Melampyrum pratenseL. (Koch) is used in traditional Austrian medicine for the treatment of different inflammation-related conditions. In this work, we show that the extracts ofM. pratensestimulated peroxisome proliferator-activated receptors- (PPARs-)αand -γthat are well recognized for their anti-inflammatory activities. Furthermore, the extract inhibited the activation of the proinflammatory transcription factor NF-κB and induction of its target genes interleukin-8 (IL-8) and E-selectinin vitro. Bioassay-guided fractionation identified several active flavonoids and iridoids including melampyroside and mussaenoside and the phenolic compound lunularin that were identified in this species for the first time. The flavonoids apigenin and luteolin were distinguished as the main components accountable for the anti-inflammatory properties. Apigenin and luteolin effectively inhibited tumor necrosis factorα(TNF-α)-induced NF-κB-mediated transactivation of a luciferase reporter gene. Furthermore, the two compounds dose-dependently reduced IL-8 and E-selectin protein expression after stimulation with lipopolysaccharide (LPS) or TNF-αin endothelial cells (ECs). The iridoids melampyroside and mussaenoside prevented the elevation of E-selectin in LPS-stimulated ECs. Lunularin was found to reduce the protein levels of the proinflammatory mediators E-selectin and IL-8 in ECs in response to LPS. These data validate the ethnomedical use ofM. pratensefor the treatment of inflammatory conditions and point to the constituents accountable for its anti-inflammatory activity.

scholarly journals Beneficial Effects of Akkermansia muciniphila Are Not Associated with Major Changes in the Circulating Endocannabinoidome but Linked to Higher Mono-Palmitoyl-Glycerol Levels as New PPARα Agonists

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 185
Author(s):  
Clara Depommier ◽  
Rosa Maria Vitale ◽  
Fabio Arturo Iannotti ◽  
Cristoforo Silvestri ◽  
Nicolas Flamand ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Univariate Analysis ◽  
Metabolic Effects ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Akkermansia Muciniphila ◽  
Beneficial Effects ◽  
Daily Ingestion ◽  
Before And After ◽  
Palmitoyl Glycerol

Akkermansia muciniphila is considered as one of the next-generation beneficial bacteria in the context of obesity and associated metabolic disorders. Although a first proof-of-concept of its beneficial effects has been established in the context of metabolic syndrome in humans, mechanisms are not yet fully understood. This study aimed at deciphering whether the bacterium exerts its beneficial properties through the modulation of the endocannabinoidome (eCBome). Circulating levels of 25 endogenous endocannabinoid-related lipids were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in the plasma of overweight or obese individuals before and after a 3 months intervention consisting of the daily ingestion of either alive or pasteurized A. muciniphila. Results from multivariate analyses suggested that the beneficial effects of A. muciniphila were not linked to an overall modification of the eCBome. However, subsequent univariate analysis showed that the decrease in 1-Palmitoyl-glycerol (1-PG) and 2-Palmitoyl-glycerol (2-PG), two eCBome lipids, observed in the placebo group was significantly counteracted by the alive bacterium, and to a lower extent by the pasteurized form. We also discovered that 1- and 2-PG are endogenous activators of peroxisome proliferator-activated receptor alpha (PPARα). We hypothesize that PPARα activation by mono-palmitoyl-glycerols may underlie part of the beneficial metabolic effects induced by A. muciniphila in human metabolic syndrome.

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