A Novel Partial Agonist of Peroxisome Proliferator-Activated Receptor-γ (PPARγ) Recruits PPARγ-Coactivator-1α, Prevents Triglyceride Accumulation, and Potentiates Insulin Signaling in Vitro

Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose–tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.

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CMHX008, a Novel Peroxisome Proliferator-Activated Receptor γ Partial Agonist, Enhances Insulin Sensitivity In Vitro and In Vivo

PLoS ONE ◽

10.1371/journal.pone.0102102 ◽

2014 ◽

Vol 9 (7) ◽

pp. e102102 ◽

Cited By ~ 8

Author(s):

Yue Ming ◽

Xiangnan Hu ◽

Ying Song ◽

Zhiguo Liu ◽

Jibin Li ◽

...

Keyword(s):

Insulin Sensitivity ◽

Partial Agonist ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

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MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema

Molecular Endocrinology ◽

10.1210/me.2008-0473 ◽

2009 ◽

Vol 23 (7) ◽

pp. 975-988 ◽

Cited By ~ 65

Author(s):

Francine M. Gregoire ◽

Fang Zhang ◽

Holly J. Clarke ◽

Thomas A. Gustafson ◽

Dorothy D. Sears ◽

...

Keyword(s):

Target Genes ◽

Partial Agonist ◽

Oral Glucose ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Sensitizer ◽

Glucose Lowering ◽

Ppar Γ ◽

Primary Mouse

Abstract MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.

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CRISPR-mediated BMP9 ablation promotes liver steatosis via the down-regulation of PPARα expression

Science Advances ◽

10.1126/sciadv.abc5022 ◽

2020 ◽

Vol 6 (48) ◽

pp. eabc5022

Author(s):

Z. Yang ◽

P. Li ◽

Q. Shang ◽

Y. Wang ◽

J. He ◽

...

Keyword(s):

Metabolic Syndrome ◽

Critical Role ◽

Liver Steatosis ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Triglyceride Accumulation

Obesity drives the development of nonalcoholic fatty liver disease (NAFLD) characterized by hepatic steatosis. Several bone morphogenetic proteins (BMPs) except BMP9 were reported related to metabolic syndrome. This study demonstrates that liver cytokine BMP9 is decreased in the liver and serum of NAFLD model mice and patients. BMP9 knockdown induces lipid accumulation in Hepa 1-6 cells. BMP9–knockout mice exhibit hepatosteatosis due to down-regulated peroxisome proliferator–activated receptor α (PPARα) expression and reduced fatty acid oxidation. In vitro, recombinant BMP9 treatment attenuates triglyceride accumulation by enhancing PPARα promoter activity via the activation of p-smad. PPARα-specific antagonist GW6471 abolishes the effect of BMP9 knockdown. Furthermore, adeno-associated virus–mediated BMP9 overexpression in mouse liver markedly relieves liver steatosis and obesity-related metabolic syndrome. These findings indicate that BMP9 plays a critical role in regulating hepatic lipid metabolism in a PPARα-dependent manner and may provide a previously unknown insight into NAFLD therapeutic approaches.

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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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Ectopic Overexpression of PPARγ2 in the Heart Determines Differences in Hypertrophic Cardiomyopathy After Treatment With Different Thiazolidinediones in a Mouse Model of Diabetes

Frontiers in Pharmacology ◽

10.3389/fphar.2021.683156 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xuemei Cao ◽

Min Mao ◽

Junlin Diao ◽

Yi Hou ◽

Hong Su ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Cardiac Hypertrophy ◽

Heart Function ◽

Partial Agonist ◽

Compensatory Hypertrophy ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Ectopic Overexpression

The clinical controversy of rosiglitazone as a hypoglycemic agent is potentially associated with heart failure, mainly due to its potent activation of peroxisome proliferator-activated receptor γ (PPARγ). PPARγ partial agonists showed superior pharmacological profiles to rosiglitazone. This study compared differences in cardiac morphology and function of the PPARγ partial agonist CMHX008 with rosiglitazone. High-fat diet (HFD) induced obese mice, ob/ob mice and cardiomyocytes overexpressing PPARγ2 were treated with CMHX008 or rosiglitazone. Heart function, myocardial morphology, and hypertrophy-related gene expression were examined. Clinical information from patients with type 2 diabetes mellitus (T2DM) who had taken rosiglitazone and undergone Doppler echocardiography was collected. HFD and ob/ob mice significantly developed cardiac contractile dysfunction, with upregulated PPARγ2 protein levels in heart tissues. Cardiomyocytes of HFD and ob/ob mice were disorderly arranged, the cell areas expanded, and collagen accumulated. In vitro cardiomyocytes overexpressing PPARγ2 displayed obvious structural abnormalities and high mRNA levels of ANP and BNP, critical cardiac hypertrophy-related genes. HFD-fed mice treated with rosiglitazone or CMHX008 had significantly improved cardiac function, but rosiglitazone induced higher expression of ANP and βMHC and hypertrophic cardiomyopathy, while CMHX008 did not. Patients with T2DM taking rosiglitazone exhibited increased thickness of the posterior wall and the ventricular septum, suggesting cardiac hypertrophy. Our findings show that diabetic cardiomyopathy was associated with ectopic overexpression of PPARγ2. The full agonist rosiglitazone prevents cardiac dysfunction at the expense of compensatory hypertrophy, while the partial agonist CMHX008 shared a comparable protective effect without altering the structure of cardiomyocytes.

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Metabolic Differences between Subcutaneous and Visceral Adipocytes Differentiated with an Excess of Saturated and Monounsaturated Fatty Acids

Genes ◽

10.3390/genes11091092 ◽

2020 ◽

Vol 11 (9) ◽

pp. 1092

Author(s):

Małgorzata Małodobra-Mazur ◽

Aneta Cierzniak ◽

Dorota Pawełka ◽

Krzysztof Kaliszewski ◽

Jerzy Rudnicki ◽

...

Keyword(s):

Fatty Acids ◽

Adipose Tissue ◽

Oleic Acid ◽

Insulin Signaling ◽

Monounsaturated Fatty Acids ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Major Health Problem ◽

Fat Depots

Obesity is a major health problem in highly industrialized countries. High-fat diet (HFD) is one of the most common causes of obesity and obesity-related disorders. There are considerable differences between fat depots and the corresponding risks of metabolic disorders. We investigated the various effects of an excess of fatty acids (palmitic 16:0, stearic 18:0, and oleic acids 18:1n−9) on adipogenesis of subcutaneous- and visceral-derived mesenchymal stem cells (MSCs) and phenotypes of mature adipocytes. MSCs of white adipose tissue were acquired from adipose tissue biopsies obtained from subcutaneous and visceral fat depots from patients undergoing abdominal surgery. The MSCs were extracted and differentiated in vitro with the addition of fatty acids. Oleic acid stimulated adipogenesis, resulting in higher lipid content and larger adipocytes. Furthermore, oleic acid stimulated adipogenesis by increasing the expression of CCAAT enhancer binding protein β (CEBPB) and peroxisome proliferator activated receptor γ (PPARG). All of the examined fatty acids attenuated the insulin-signaling pathway and radically reduced glucose uptake following insulin stimulation. Visceral adipose tissue was shown to be more prone to generate inflammatory stages. The subcutaneous adipose tissue secreted a greater quantity of adipokines. To summarize, oleic acid showed the strongest effect on adipogenesis. Furthermore, all of the examined fatty acids attenuated insulin signaling and secretion of cytokines and adipokines.

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miR-381 Targets KCTD15 to Regulate Bovine Preadipocyte Differentiation In Vitro

Hormone and Metabolic Research ◽

10.1055/a-1276-1602 ◽

2020 ◽

Vol 53 (01) ◽

pp. 63-70

Author(s):

Hongyan Xu ◽

Jing Shao ◽

Jiachen Fang ◽

Baozhen Yin ◽

Luomeng Zhang ◽

...

Keyword(s):

Fat Metabolism ◽

Regulation Of Gene Expression ◽

Luciferase Reporter ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Triglyceride Accumulation ◽

Fat Deposits ◽

Yellow Cattle

AbstractMicroRNAs (miRNAs) are small, single-stranded, noncoding RNAs ~21 to ~23 nucleotides in length and have become a popular research topic in recent years due to their regulation of gene expression and many physiological processes, including fat metabolism; however, the precise functional mechanisms underlying their regulation of fat metabolism are not fully understood. Here, we identified miR-381, which specifically targets the 3′ untranslated region (3′ UTR) of potassium channel tetramerization-domain-containing 15 (KCTD15) , and verified the mechanism regulating its expression and participation in adipogenesis. We used a dual luciferase-reporter assay and transfection-mediated miR-381 overexpression and inhibition in Yanbian yellow cattle preadipocytes to investigate the role of miR-381 in adipogenesis. The results showed that miR-381 directly targets the 3′ UTR of KCTD15 and downregulates its expression. Additionally, miR-381 overexpression using an miRNA mimic promoted triglyceride accumulation and upregulated adipogenic peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer-binding protein α (C/EBPα) at both the protein and mRNA levels, whereas miR-381 inhibition produced the opposite effect. These results indicated that miR-381 regulates the differentiation of Yanbian yellow cattle preadipocytes by inhibiting KCTD15 expression, thereby highlighting the importance of miRNA-mediated regulation of adipogenesis. Furthermore, our findings suggested that miR-381 and its target gene(s) might represent new targets for investigating intramuscular fat deposits in cattle and treating human obesity.

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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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