Exercise Training-Induced PPARβ Increases PGC-1α Protein Stability and Improves Insulin-Induced Glucose Uptake in Rodent Muscles

This study aimed to investigate the long-term effects of training intervention and resting on protein expression and stability of peroxisome proliferator-activated receptor β/δ (PPARβ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), glucose transporter type 4 (GLUT4), and mitochondrial proteins, and determine whether glucose homeostasis can be regulated through stable expression of these proteins after training. Rats swam daily for 3, 6, 9, 14, or 28 days, and then allowed to rest for 5 days post-training. Protein and mRNA levels were measured in the skeletal muscles of these rats. PPARβ was overexpressed and knocked down in myotubes in the skeletal muscle to investigate the effects of swimming training on various signaling cascades of PGC-1α transcription, insulin signaling, and glucose uptake. Exercise training (Ext) upregulated PPARβ, PGC-1α, GLUT4, and mitochondrial enzymes, including NADH-ubiquinone oxidoreductase (NUO), cytochrome c oxidase subunit I (COX1), citrate synthase (CS), and cytochrome c (Cyto C) in a time-dependent manner and promoted the protein stability of PPARβ, PGC-1α, GLUT4, NUO, CS, and Cyto C, such that they were significantly upregulated 5 days after training cessation. PPARβ overexpression increased the PGC-1α protein levels post-translation and improved insulin-induced signaling responsiveness and glucose uptake. The present results indicate that Ext promotes the protein stability of key mitochondria enzymes GLUT4, PGC-1α, and PPARβ even after Ext cessation.

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Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells

Journal of Endocrinology ◽

10.1677/joe-07-0138 ◽

2007 ◽

Vol 194 (1) ◽

pp. 87-99 ◽

Cited By ~ 35

Author(s):

Masaya Takeda ◽

Fumio Otsuka ◽

Hiroyuki Otani ◽

Kenichi Inagaki ◽

Tomoko Miyoshi ◽

...

Keyword(s):

Cell Proliferation ◽

Receptor Activation ◽

Bmp Signaling ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Dependent Manner ◽

Fenofibric Acid ◽

Peroxisome Proliferator Activated Receptor ◽

Bmp Receptors ◽

Cell Mitosis

Involvement of peroxisome proliferator-activated receptor-γ (PPAR-γ ) activation and bone morphogenetic protein (BMP) signaling in regulating cell proliferation and hormonal production of pituitary tumors has been reported, although the underlying mechanism remains poorly understood. Here, we investigated regulatory roles of PPARα and PPARγ in gonadotropin transcription and cell mitosis modulated by pituitary activin/BMP systems using a mouse gonadotropinoma cell line Lβ T2, which expresses activin/BMP receptors, transcription factor Smads, PPARα , and PPARγ . In Lβ T2 cells, BMP signaling shown by Smad1/5/8 phosphorylation and Id-1 transcription was readily activated by BMPs. A PPARγ agonist, pioglitazone significantly reduced BMP-induced DNA synthesis by Lβ T2; whereas the PPARα agonist, fenofibric acid, did not. In accordance with the effects on cell mitosis, pioglitazone but not fenofibric acid significantly decreased BMP-induced Id-1-Luc activation. Neither fenofibric acid nor pioglitazone affected activin signaling detected by (CAGA)9-Luc activity. Both PPARα and PPARγ ligands directly suppressed transcriptional activities of FSHβ , LHβ , and GnRHR. Activation of PPARα and PPARγ increased mRNA levels of follistatin, but did not affect the expression of follistatin-related gene. Thus, PPAR agonists not only directly suppress gonadotropin transcription and BMP signaling, but also inhibit the biological actions of activins which facilitate gonadotropin transcription through upregulating follistatin expression. In addition, pioglitazone increased BMP ligands mRNA, but decreased activin-β B mRNA in Lβ T2 cells. Collectively, PPAR activation differentially regulates gonadotrope cell proliferation and gonadotropin transcription in a ligand-dependent manner.

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Abstract 1729: PPARγ Regulates ABCG1 Expression in Macrophages via LXR-Driven Dual Promoters

Circulation ◽

10.1161/circ.118.suppl_18.s_378 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Makoto Ayaori ◽

Masatsune Ogura ◽

Kazuhiro Nakaya ◽

Tetsuya Hisada ◽

Shun-ichi Takiguchi ◽

...

Keyword(s):

Cholesterol Efflux ◽

Density Lipoprotein ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

Exon 1 ◽

Dual Promoters ◽

Sirna Knockdown

ATP binding cassette transporter G1 (ABCG1), which is expressed in macrophages, has been implicated in the efflux of cholesterol to high density lipoprotein. Peroxisome proliferator-activated receptor γ (PPARγ) has been reported to be involved in cholesterol efflux from macrophages, and increased expression of ABCG1 via liver receptor X (LXR)-dependent and independent pathways. However, the mechanisms by which ABCG1 expression is increased by PPARγ have not been fully characterized. We observed that pioglitazone, a PPARγ ligand, increases cholesterol efflux from THP-1 macrophages, as well as ABCG1 mRNA and protein levels. Treatment with actinomycin D abolished the inducible effect of pioglitazone on ABCG1, indicating that pioglitazone transcriptionally activated ABCG1 expression. To clarify how pioglitazone regulates ABCG1 expression, we investigated promoter activity using reporter constructs containing human ABCG1 promoter A and B (located upstream of exon 1 and 5, respectively), with or without mutated LXR-binding sites. The results indicated that pioglitazone activated both promoters in an LXR-dependent manner. We also observed that pioglitazone increased two major transcripts driven by promoter A and B using specific primers for each transcript. To determine whether PPARγ and LXRα were involved in these effects of pioglitazone, we performed siRNA-knockdown of PPARγ and LXRα in macrophages, which resulted in 75% and 91% decreases in PPARγ and LXRα mRNA levels, respectively. PPARγ and LXRα-knockdown, respectively, completely or partially abolished pioglitazone-induced ABCG1 expression. In conclusion, these results suggest that pioglitazone transcriptionally increased ABCG1 expression in macrophages by activating dual promoters in an LXR-dependent manner. Further studies are needed to assess LXR-independent mechanisms for the stimulatory effect of pioglitazone on ABCG1.

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Quercetin Inhibits Inflammatory Response Induced by LPS from Porphyromonas gingivalis in Human Gingival Fibroblasts via Suppressing NF-κB Signaling Pathway

BioMed Research International ◽

10.1155/2019/6282635 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Gang Xiong ◽

Wansheng Ji ◽

Fei Wang ◽

Fengxiang Zhang ◽

Peng Xue ◽

...

Keyword(s):

Porphyromonas Gingivalis ◽

Interleukin 1 ◽

Human Gingival Fibroblasts ◽

Enzyme Linked Immunosorbent Assay ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Dependent Manner ◽

Gingival Fibroblasts ◽

Peroxisome Proliferator Activated Receptor ◽

Anti Inflammatory

Quercetin, a natural flavonol existing in many food resources, has been reported to be an effective antimicrobial and anti-inflammatory agent for restricting the inflammation in periodontitis. In this study, we aimed to investigate the anti-inflammatory effects of quercetin on Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide- (LPS-) stimulated human gingival fibroblasts (HGFs). HGFs were pretreated with quercetin prior to LPS stimulation. Cell viability was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The levels of inflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), along with chemokine interleukin-8 (IL-8), were determined by enzyme-linked immunosorbent assay (ELISA). The mRNA levels of IL-1β, IL-6, IL-8, TNF-α, IκBα, p65 subunit of nuclear factor-kappa B (NF-κB), peroxisome proliferator-activated receptor-γ (PPAR-γ), liver X receptor α (LXRα), and Toll-like receptor 4 (TLR4) were measured by real-time quantitative PCR (RT-qPCR). The protein levels of IκBα, p-IκBα, p65, p-p65, PPAR-γ, LXRα, and TLR4 were characterized by Western blotting. Our results demonstrated that quercetin inhibited the LPS-induced production of IL-1β, IL-6, IL-8, and TNF-α in a dose-dependent manner. It also suppressed LPS-induced NF-κB activation mediated by TLR4. Moreover, the anti-inflammatory effects of quercetin were reversed by the PPAR-γ antagonist of GW9662. In conclusion, these results suggested that quercetin attenuated the production of IL-1β, IL-6, IL-8, and TNF-α in P. gingivalis LPS-treated HGFs by activating PPAR-γ which subsequently suppressed the activation of NF-κB.

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AMPK and PPARβ positive feedback loop regulates endurance exercise training-mediated GLUT4 expression in skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00460.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. E931-E939 ◽

Cited By ~ 6

Author(s):

Jin-Ho Koh ◽

Chad R. Hancock ◽

Dong-Ho Han ◽

John O. Holloszy ◽

K. Sreekumaran Nair ◽

...

Keyword(s):

Skeletal Muscle ◽

Exercise Training ◽

Glucose Uptake ◽

Glucose Transporter ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Glut4 Expression ◽

Amp Activated Protein Kinase ◽

Response To Exercise ◽

Glucose Transporter Type 4

The objective of this study is to determine whether AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), or peroxisome proliferator-activated receptor β (PPARβ) can independently mediate the increase of glucose transporter type 4 (GLUT4) expression that occurs in response to exercise training. We found that PPARβ can regulate GLUT4 expression without PGC-1α. We also found AMPK and PPARβ are important for maintaining normal physiological levels of GLUT4 protein in the sedentary condition as well following exercise training. However, AMPK and PPARβ are not essential for the increase in GLUT4 protein expression that occurs in response to exercise training. We discovered that AMPK activation increases PPARβ via myocyte enhancer factor 2A (MEF2A), which acted as a transcription factor for PPARβ. Furthermore, exercise training increases the cooperation of AMPK and PPARβ to regulate glucose uptake. In conclusion, cooperation between AMPK and PPARβ via NRF-1/MEF2A pathway enhances the exercise training mediated adaptive increase in GLUT4 expression and subsequent glucose uptake in skeletal muscle.

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Molecular mechanism of 1,25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00410.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. E916-E924 ◽

Cited By ~ 179

Author(s):

Juan Kong ◽

Yan Chun Li

Keyword(s):

Cell Differentiation ◽

Molecular Mechanism ◽

Regulatory Element ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Dependent Manner ◽

Dihydroxyvitamin D3 ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels

We have investigated the molecular mechanism whereby 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits adipogenesis in vitro. 1,25(OH)2D3 blocks 3T3-L1 cell differentiation into adipocytes in a dose-dependent manner; however, the inhibition is ineffective 24–48 h after the differentiation is initiated, suggesting that 1,25(OH)2D3 inhibits only the early events of the adipogenic program. Treatment of 3T3-L1 cells with 1,25(OH)2D3 does not block the mitotic clonal expansion or C/EBPβ induction; rather, 1,25(OH)2D3 blocks the expression of C/EBPα, peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1, and other downstream adipocyte markers. The inhibition by 1,25(OH)2D3 is reversible, since removal of 1,25(OH)2D3 from the medium restores the adipogenic process with only a temporal delay. Interestingly, although the vitamin D receptor (VDR) protein is barely detectable in 3T3-L1 preadipocytes, its levels are dramatically increased during the early phase of adipogenesis, peaking at 4–8 h and subsiding afterward throughout the rest of the differentiation program; 1,25(OH)2D3 treatment appears to stabilize the VDR protein levels. Consistently, adenovirus-mediated overexpression of human (h) VDR in 3T3-L1 cells completely blocks the adipogenic program, confirming that VDR is inhibitory. Inhibition of adipocyte differentiation by 1,25(OH)2D3 is ameliorated by troglitazone, a specific PPARγ antagonist; conversely, hVDR partially suppresses the transacting activity of PPARγ but not of C/EBPβ or C/EBPα. Moreover, 1,25(OH)2D3 markedly suppresses C/EBPα and PPARγ mRNA levels in mouse epididymal fat tissue culture. Taken together, these data indicate that the blockade of 3T3-L1 cell differentiation by 1,25(OH)2D3 occurs at the postclonal expansion stages and involves direct suppression of C/EBPα and PPARγ upregulation, antagonization of PPARγ activity, and stabilization of the inhibitory VDR protein.

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Hepatic Cerebroside Sulfotransferase Is Induced by PPARα Activation in Mice

PPAR Research ◽

10.1155/2012/174932 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 8

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.

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Thyroid hormone interacts with PPARα and PGC-1 during mitochondrial maturation in sheep heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00473.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. H2258-H2264 ◽

Cited By ~ 21

Author(s):

Timothy D. McClure ◽

Martin E. Young ◽

Heinrich Taegtmeyer ◽

Xue-Han Ning ◽

Norman E. Buroker ◽

...

Keyword(s):

Thyroid Hormone ◽

Cytochrome C ◽

Target Genes ◽

Steroid Receptors ◽

Pyruvate Dehydrogenase Kinase ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Postnatal Maturation

Thyroid hormone (TH) promotes cardiac mitochondrial maturation and substrate metabolism after birth. This regulation involves ligand-dependent binding of nuclear TH receptors to target gene elements. TH also putatively controls genes indirectly by modulating transcription and/or translation of other nuclear steroid receptors and coactivators, such as peroxisome proliferator-activated receptor-α (PPARα) and peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1). We tested the hypothesis that TH influences PPARα and PGC-1 regulation of metabolic genes during postnatal maturation in sheep heart in vivo. We measured their mRNAs and/or protein levels and downstream targets in left ventricle from lambs: fetal (F), 30-day-old after postnatal thyroidectomy (THY), and 30-day-old euthyroid (Con). Both PPARα and PGC-1 mRNA expression decreased from F to Con, while PGC-1 protein increased substantially and PPARα did not change. THY limited this mRNA response and attenuated the paradoxical postnatal PGC-1 protein elevation but did not alter mRNA levels for PPARα, nuclear respiratory factor-1 and hypoxia-inducible factor-1α. THY promotion in PPARα mRNA did not change PPARα protein or mRNA for PPARα target genes, pyruvate-dehydrogenase kinase 4 ( PDK4) and muscle type carnitine palmitoyltransferase I ( mCPTI). THY reduction in PGC-1 protein occurred, while reducing cytochrome c oxidase and cytochrome c content and decreasing cardiac maximal inherent respiratory capacity. These data imply that TH modulates mitochondrial maturation partly through posttranscriptional control of PGC-1, while any important regulation of PDK4 and mCPTI by change in PPARα protein expression remains doubtful. Also, the paradoxical expression pattern between mRNA and protein, particularly for PGC-1, suggests a feedback control mechanism.

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Exercise training increases mitochondrial biogenesis in the brain

Journal of Applied Physiology ◽

10.1152/japplphysiol.00343.2011 ◽

2011 ◽

Vol 111 (4) ◽

pp. 1066-1071 ◽

Cited By ~ 152

Author(s):

Jennifer L. Steiner ◽

E. Angela Murphy ◽

Jamie L. McClellan ◽

Martin D. Carmichael ◽

J. Mark Davis

Keyword(s):

Exercise Training ◽

Mitochondrial Biogenesis ◽

Citrate Synthase ◽

Brain Mitochondria ◽

Brain Regions ◽

Treadmill Running ◽

Endurance Capacity ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Age Related

Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions ( n = 16–19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice ( n = 9–11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice ( n = 7–8/group) performed a treadmill RTF test. Exercise training increased PGC-1α, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus ( P < 0.05). Mean treadmill RTF increased from 74.0 ± 9.6 min to 126.5 ± 16.1 min following training ( P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction.

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Inhibition of Adipogenesis by Oligonol through Akt-mTOR Inhibition in 3T3-L1 Adipocytes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2014/895272 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 10

Author(s):

Jae-Yeo Park ◽

Younghwa Kim ◽

Jee Ae Im ◽

Seungkwon You ◽

Hyangkyu Lee

Keyword(s):

Signaling Pathway ◽

Mammalian Target Of Rapamycin ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Dependent Manner ◽

Mtor Inhibition ◽

Peroxisome Proliferator Activated Receptor ◽

Downstream Target ◽

Ribosomal Protein S6 ◽

Expression Of Genes

Polyphenols have recently become an important focus of study in obesity research. Oligonol is an oligomerized polyphenol, typically comprised of catechin-type polyphenols from a variety of fruits, which has been found to exhibit better bioavailability and bioreactivity than natural polyphenol compounds. Here, we demonstrated that Oligonol inhibits 3T3-L1 adipocyte differentiation by reducing adipogenic gene expression. During adipogenesis, Oligonol downregulated the mRNA levels of peroxisome proliferator-activated receptorγ(PPARγ), CCAAT/enhancer binding proteins α (C/EBPα), andδ(C/EBPδ) in a dose-dependent manner and the expression of genes involved in lipid biosynthesis. The antiadipogenic effect of Oligonol appears to originate from its ability to inhibit the Akt and mammalian target of rapamycin (mTOR) signaling pathway by diminishing the phosphorylation of ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR and forkhead box protein O1 (Foxo1). These results suggest that Oligonol may be a potent regulator of obesity by repressing major adipogenic genes through inhibition of the Akt signaling pathway, which induces the inhibition of lipid accumulation, ultimately inhibiting adipogenesis.

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Apoptosis in Human Oral Squamous Cell Carcinomas is Induced by 15-Deoxy-Δ12,14-Prostaglandin J2 but not by Troglitazone

Journal of Dental Research ◽

10.1177/154405910308201008 ◽

2003 ◽

Vol 82 (10) ◽

pp. 802-806 ◽

Cited By ~ 10

Author(s):

K. Fukuchi ◽

M. Date ◽

Y. Azuma ◽

M. Shinohara ◽

H. Takahashi ◽

...

Keyword(s):

Cytochrome C ◽

Cell Lines ◽

Squamous Cell ◽

Squamous Cell Carcinomas ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Caspase Activation ◽

Cytochrome C Release ◽

Peroxisome Proliferator Activated Receptor ◽

Oral Squamous Cell Carcinomas

15-deoxy-Δ12,14-prostaglandin J2 (15-d-PGJ2) and troglitazone have been shown to induce apoptosis in several carcinoma cell lines. However, apoptotic signaling pathways of these agents are poorly understood. We tested the hypothesis that peroxisome proliferator-activated receptor-γ ligands such as these two agents will induce caspase-mediated apoptosis in human oral squamous cell carcinomas (SCC). Treatment of these cell lines with 15-d-PGJ2 or troglitazone decreased cell viability in a time- and dose-dependent manner. 15-d-PGJ2, but not troglitazone, induced apoptosis, and this effect was time-dependent. Exposure of cells to 20 μM of 15-d-PGJ2 initiated early cytochrome c release, followed by late caspase activation. Furthermore, co-treatment with caspase inhibitors such as Z-VAD-FMK or Z-DEVD-FMK of oral SCC cells that had been treated with 20 μM of 15-d-PGJ2 blocked apoptosis. Our study demonstrates that treatment with 15-d-PGJ2, but not troglitazone, induces apoptosis in human SCC cell lines, and 15-d-PGJ2 appears to work through cytochrome c release and caspase activation.

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