Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Rosiglitazone Suppresses Components of the Insulin-Like Growth Factor Regulatory System in Vitro and in Vivo

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor γ (PPARγ). Stimulation of PPARγ suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARγ down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 μm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARγ2 (U-33/γ2) were analyzed by microarray. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and II IGF receptor (IGF1R and IGF2R) expression at 72 h in U-33/γ2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/γ2 cells by 75% (P < 0.05). Primary marrow stromal cells (MSCs) extracted from adult (8 months) and old (24 months) C57BL/6J (B6) mice were treated with Rosi (1 μm) for 48 h. IGF-I, IGFBP-4, and IGF1R transcripts were reduced in Rosi-treated MSCs compared with vehicle (P < 0.01) and secreted IGF-I was also suppressed (P < 0.05). B6 mice treated with Rosi (20 mg/kg·d) for short duration (i.e. 4 d), and long term (i.e. 7 wk) had reduced serum IGF-I; this was accompanied by markedly suppressed IGF-I transcripts in the liver and peripheral fat of treated animals. To determine whether Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2, and IGFBP-3 at four time points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi-treated subjects had significantly lower IGF-I at 8 wk than baseline (−25%, P < 0.05), and at 16 wk their levels were reduced 14% vs. placebo (P = 0.15). We conclude that Rosi suppresses IGF-I expression in bone and liver; these changes could affect skeletal acquisition through endocrine and paracrine pathways.

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Long-term fasting decreases mitochondrial avian UCP-mediated oxygen consumption in hypometabolic king penguins

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00271.2007 ◽

2008 ◽

Vol 295 (1) ◽

pp. R92-R100 ◽

Cited By ~ 12

Author(s):

Benjamin Rey ◽

Lewis G. Halsey ◽

Virginie Dolmazon ◽

Jean-Louis Rouanet ◽

Damien Roussel ◽

...

Keyword(s):

Oxygen Consumption ◽

Metabolic Rate ◽

Metabolic Efficiency ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

The Difference ◽

Reduced Rate

In endotherms, regulation of the degree of mitochondrial coupling affects cell metabolic efficiency. Thus it may be a key contributor to minimizing metabolic rate during long periods of fasting. The aim of the present study was to investigate whether variation in mitochondrial avian uncoupling proteins (avUCP), as putative regulators of mitochondrial oxidative phosphorylation, may contribute to the ability of king penguins ( Aptenodytes patagonicus) to withstand fasting for several weeks. After 20 days of fasting, king penguins showed a reduced rate of whole animal oxygen consumption (V̇o2; −33%) at rest, together with a reduced abundance of avUCP and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1-α) mRNA in pectoralis muscle (−54%, −36%, respectively). These parameters were restored after the birds had been refed for 3 days. Furthermore, in recently fed, but not in fasted penguins, isolated muscle mitochondria showed a guanosine diphosphate-inhibited, fatty acid plus superoxide-activated respiration, indicating the presence of a functional UCP. It was calculated that variation in mitochondrial UCP-dependent respiration in vitro may contribute to nearly 20% of the difference in resting V̇o2 between fed or refed penguins and fasted penguins measured in vivo. These results suggest that the lowering of avUCP activity during periods of long-term energetic restriction may contribute to the reduction in metabolic rate and hence the ability of king penguins to face prolonged periods of fasting.

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circRNA_0046367 Prevents Hepatoxicity of Lipid Peroxidation: An Inhibitory Role against Hepatic Steatosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/3960197 ◽

2017 ◽

Vol 2017 ◽

pp. 1-16 ◽

Cited By ~ 23

Author(s):

Xing-Ya Guo ◽

Jian-Neng Chen ◽

Fang Sun ◽

Yu-Qin Wang ◽

Qin Pan ◽

...

Keyword(s):

Lipid Peroxidation ◽

Hepatic Steatosis ◽

Transcriptional Activation ◽

Regulatory System ◽

Inhibitory Effect ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Triglyceride Accumulation

Hepatic steatosis reflects the miRNA-related pathological disorder with triglyceride accumulation and lipid peroxidation, which leads to nonalcoholic steatohepatitis, liver fibrosis/cirrhosis, and even hepatocellular carcinoma. Circular RNA (circRNA)/miRNA interaction reveals a novel layer of epigenetic regulation, yet the miRNA-targeting circRNA remains uncertain in hepatic steatosis. Here, we uncover circRNA_0046367 to be endogenous modulator of miR-34a that underlies hepatic steatosis. In contrast to its expression loss during the hepatocellular steatosis in vivo and in vitro, circRNA_0046367 normalization abolished miR-34a’s inhibitory effect on peroxisome proliferator-activated receptorα(PPARα) via blocking the miRNA/mRNA interaction with miRNA response elements (MREs). PPARαrestoration led to the transcriptional activation of genes associated with lipid metabolism, including carnitine palmitoyltransferase 2 (CPT2) and acyl-CoA binding domain containing 3 (ACBD3), and then resulted in the steatosis resolution. Hepatotoxicity of steatosis-related lipid peroxidation, being characterized by mitochondrial dysfunction, growth arrest, and apoptosis, is resultantly prevented after the circRNA_0046367 administration. These findings indicate a circRNA_0046367/miR-34a/PPARαregulatory system underlying hepatic steatosis. Normalized expression of circRNA_0046367 may ameliorate the lipoxidative stress on the basis of steatosis attenuation. circRNA_0046367, therefore, is suggested to be potential approach to the therapy of lipid peroxidative damage.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽

10.1186/s12885-021-08417-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Zhu ◽

Hongyang Zhao ◽

Fenfen Xu ◽

Bin Huang ◽

Xiaojing Dai ◽

...

Keyword(s):

Noncoding Rna ◽

Glioma Cells ◽

Lipid Lowering ◽

Fibric Acid Derivative ◽

Peroxisome Proliferator ◽

Glioma Invasion ◽

Peroxisome Proliferator Activated Receptor ◽

Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

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The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Inhibit IL-6 or TNF-α Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo

The Journal of Immunology ◽

10.4049/jimmunol.164.2.1046 ◽

2000 ◽

Vol 164 (2) ◽

pp. 1046-1054 ◽

Cited By ~ 139

Author(s):

Rolf Thieringer ◽

Judy E. Fenyk-Melody ◽

Cheryl B. Le Grand ◽

Beverly A. Shelton ◽

Patricia A. Detmers ◽

...

Keyword(s):

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α

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Suppression of Peroxisome Proliferator-Activated Receptor γ-Coactivator-1α Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Endocrinology ◽

10.1210/en.2009-0241 ◽

2009 ◽

Vol 150 (9) ◽

pp. 4074-4083 ◽

Cited By ~ 10

Author(s):

Ji-Won Kim ◽

Young-Hye You ◽

Dong-Sik Ham ◽

Jae-Hyoung Cho ◽

Seung-Hyun Ko ◽

...

Keyword(s):

Glucose Tolerance ◽

Receptor Site ◽

Diabetic Rats ◽

Peroxisome Proliferator ◽

Β Cells ◽

Β Cell ◽

Peroxisome Proliferator Activated Receptor ◽

Cell Dysfunction

Abstract Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1α in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1α in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1α in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1α also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1α small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1α but were rescued by Ad-siPGC-1α. PGC-1α binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1α. Ad-siPGC-1α injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1α expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1α, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.

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Irisin in the primate hypothalamus and its effect on GnRH in vitro

Journal of Endocrinology ◽

10.1530/joe-18-0574 ◽

2019 ◽

Vol 241 (3) ◽

pp. 175-187 ◽

Cited By ~ 6

Author(s):

Fazal Wahab ◽

Ikram Ullah Khan ◽

Ignacio Rodriguez Polo ◽

Hira Zubair ◽

Charis Drummer ◽

...

Keyword(s):

Rhesus Monkeys ◽

Peroxisome Proliferator ◽

Developmentally Regulated ◽

Peroxisome Proliferator Activated Receptor ◽

Reproductive Effects ◽

Reproductive Axis ◽

Hypothalamic Cells ◽

Endocrine Factor

Irisin, encoded by the FNDC5 gene, is a recently discovered endocrine factor mainly secreted as a myokine and adipokine. However, irisin/FNDC5 expression has also been reported in different other organs including components of the reproductive axis. Yet, there is the scarcity of data on FNDC5/irisin expression, regulation and its reproductive effects, particularly in primates. Here, we report the expression of FNDC5/irisin, along with PGC1A (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and ERRA (estrogen-related receptor alpha), in components of the reproductive axis of marmoset monkeys. Hypothalamic FNDC5 and ERRA transcript levels are developmentally regulated in both male and female. We further uncovered sex-specific differences in FNDC5, ERRA and PGC1A expression in muscle and the reproductive axis. Moreover, irisin and ERRα co-localize in the marmoset hypothalamus. Additionally, in the arcuate nucleus of rhesus monkeys, the number of irisin+ cells was significantly increased in short-term fasted monkeys as compared to ad libitum-fed monkeys. More importantly, we observed putative interaction of irisin-immunoreactive fibers and few GnRH-immunoreactive cell bodies in the mediobasal hypothalamus of the rhesus monkeys. Functionally, we noted a stimulatory effect of irisin on GnRH synthesis and release in mouse hypothalamic neuronal GT1-7 cells. In summary, our findings show that FNDC5 and irisin are developmentally, metabolic-status dependently and sex-specifically expressed in the primate hypothalamic–pituitary–gonadal axis and exert a stimulatory effect on GnRH expression and release in mouse hypothalamic cells. Further studies are required to confirm the reproductive effects of irisin in vivo and to illuminate the mechanisms of its regulation.

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Liraglutide suppresses obesity and promotes browning of white fat via miR-27b in vivo and in vitro

Journal of International Medical Research ◽

10.1177/03000605211055059 ◽

2021 ◽

Vol 49 (11) ◽

pp. 030006052110550

Author(s):

Xing Wang ◽

Shuchun Chen ◽

Dan Lv ◽

Zelin Li ◽

Luping Ren ◽

...

Keyword(s):

Uncoupling Protein ◽

Density Lipoprotein ◽

Peroxisome Proliferator ◽

Sprague Dawley ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Levels ◽

White Adipocytes ◽

White Fat

Objective To investigate the effect of liraglutide on the browning of white fat and the suppression of obesity via regulating microRNA (miR)-27b in vivo and in vitro. Methods Sprague-Dawley rats were fed a high-fat (HF) diet and 3T3-L1 pre-adipocytes were differentiated into mature white adipocytes. Rats and mature adipocytes were then treated with different doses of liraglutide. The mRNA and protein levels of browning-associated proteins, including uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16), CCAAT enhancer binding protein β (CEBPβ), cell death-inducing DFFA-like effector A (CIDEA) and peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α), were detected using quantitative real-time polymerase chain reaction and Western blotting. Results Liraglutide decreased body weight and reduced the levels of blood glucose, triglyceride and low-density lipoprotein cholesterol in HF diet-fed rats. Liraglutide increased the levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α in vivo and vitro. The levels of miR-27b were upregulated in HF diet-fed rats, whereas liraglutide reduced the levels of miR-27b. In vitro, overexpression of miR-27b decreased the mRNA and protein levels of UCP1, PRDM16, CEBPβ, CIDEA and PGC-1α. Transfection with the miR-27b mimics attenuated the effect of liraglutide on the browning of white adipocytes. Conclusion Liraglutide induced browning of white adipose through regulation of miR-27b.

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Targeting the EZH2-PPAR Axis Is a Potential Therapeutic Pathway for Pancreatic Cancer

PPAR Research ◽

10.1155/2021/5589342 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Jilong Hu ◽

Zhinan Zheng ◽

Jia Lei ◽

Yuxin Cao ◽

Qiyun Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cyclin D1 ◽

Caspase 3 ◽

Synergistic Effects ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Agonist ◽

Combined Use

Enhancer of zeste homolog 2 (EZH2) is abnormally highly expressed in pancreatic cancer (PC). However, it is not ideal to treat PC by inhibiting EZH2. This study reported that the combined use of pan-peroxisome proliferator-activated receptor (PPAR) agonist could significantly improve the anti-PC effect of EZH2 inhibitor. In vitro, PC cell lines PANC-1 and AsPC-1 were cultured, and MTT and flow cytometry were performed to observe the effects of pan-PPAR agonist bezafibrate and EZH2 selective inhibitor GSK126 on cell viability and apoptosis. In vivo, CDXs of PANC-1 and AsPC-1 were established to observe the effects of bezafibrate and GSK126 on bearing tumors. Western blotting was performed to detect the protein expressions of H3K27me3, β-catenin, p-β-catenin, cyclin D1, c-Myc, and cleaved caspase 3 in vitro and in vivo. The results showed that bezafibrate significantly improved the effects of GSK126 on proliferation inhibition and apoptosis promotion in vitro and the growth suppression of CDX tumors in vivo. It also significantly enhanced the effects of GSK126 on upregulating the expression level of p-β-catenin and that of cleaved caspase 3 in vitro and in vivo. In parallel, downregulation of the expression levels of H3K27me3, β-catenin, cyclin D1, and c-Myc was also observed in vitro or in vivo. These results suggest that the combination of bezafibrate and GSK126 has synergistic effects on PC, and the molecular mechanism may be related to the enhanced inhibition of the Wnt/β-catenin signaling pathway. We believe that targeting the EZH2-PPAR axis is a potential therapeutic pathway for PC.

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