Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice

Silva-Veiga, Flávia Maria; Graus-Nunes, Francielle; Rachid, Tamiris Lima; Barreto, Aline Barcellos; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

doi:10.1016/j.biochi.2017.07.003

Cited by 56 publications

(38 citation statements)

References 55 publications

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“…Taken together, these findings suggest that the identified miRNA-targeted genes contribute to regulating genes and pathways that are involved in adipogenesis, which may help to define the fat deposition differences between two groups of pigs. Recently, it has been shown that targeting PPARs is a potential way to treat NAFLDs [63,64]. Since the miRNAs that we uncovered in our study regulate the PPAR pathway, this study helps us understand the players involved in the regulation of this pathway and could provide insights into better treatment for NAFLDs.…”

Section: Discussionmentioning

confidence: 63%

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

Zhang¹,

Huang²,

Guo³

et al. 2017

Oncotarget

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The domestic pig, an important species in the animal production industry, is also a model system for studying fat deposition and fat-associated diseases in humans. In order to investigate the genetic relationships of the miRNAs that may regulate fat deposition, we performed a genome-wide analysis of miRNAs derived from subcutaneous adipose tissue of Laiwu and Large White pig using RNA-seq. A total of 26,486,906 reads were obtained. Further analysis indicated that 39 known miRNAs and 56 novel miRNAs had significantly differential expression between the two breeds of pigs. Gene Ontology and KEGG pathway analysis revealed that the predicted targets of these differentially expressed miRNAs were involved in several fat-associated pathways, such as the PPAR, MAPK and Wnt signaling pathways. In addition, we found that three miRNAs, ssc-miR-133a-3p, ssc-miR-486 and ssc-miR-1, had an impact on the development of porcine subcutaneous fat through the PPAR signaling pathway. This study provides clues to understand the potential mechanisms of adipogenesis and fat deposition between two different pig breeds. Furthermore, these results may also contribute to the research involving human obesity.

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Section: Discussionmentioning

confidence: 63%

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

Zhang¹,

Huang²,

Guo³

et al. 2017

Oncotarget

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“…Fragments of liver tissue (1 mm 3 ) were fixed in 2.5 % glutaraldehyde in 0.1 M cacodylate buffer (pH 7.2) for 2 h at room temperature [32]. HepG2 cells were collected and prepared as described previously [30].…”

Section: Transmission Electron Microscopymentioning

confidence: 99%

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Zhou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Lipid droplets (LDs) are dynamic organelles that store neutral lipids during times of energy excess, and an increased accumulation of LDs in the liver is closely linked to hepatic steatosis. Our previous studies suggested that resveratrol (RSV) supplement could improve hepatic steatosis, but the underlying mechanism, particularly which related to LD accumulation, has not yet been elucidated. Methods: A high-fat diet (HFD) and palmitic acid were used to induce hepatic steatosis in mouse liver and hepatocytes, respectively. The effects of RSV on LD accumulation were analyzed in vivo and in vitro. The effects of RSV on the expression levels of LD-associated genes (ATF6, Fsp27β/CIDEC, CREBH, and PLIN1) were measured by qRT-PCR and western blot assays, followed by KD or overexpression of SIRT1 and ATF6 with small interfering RNAs or overexpressed plasmids, respectively. The dual luciferase reporter assay, chromatin immunoprecipitation assay, coimmunoprecipitation, and proximity ligation assay were utilized to clarify the mechanism of transcriptional regulation and possible interaction between SIRT1 and ATF6. Results: There was a significant increase in the accumulation of LDs in liver and hepatocytes during the process of HFD-induced steatosis, respectively, which was significantly inhibited by RSV supplementation. RSV notably activated SIRT1 expression and decreased the expression levels of ATF6, Fsp27β/CIDEC, CREBH, and PLIN1, which are associated with LD accumulation. Interestingly, the inhibitory effects of RSV on LD accumulation and the associated expression of genes in hepatocytes were abrogated or strengthened with SIRT1 silencing or overexpression, respectively. On the contrary, the benefits of RSV in hepatocytes were eliminated or aggravated when transfected with the overexpressed ATF6 or ATF6 siRNA, respectively. Furthermore, we found that RSV stimulated SIRT1 expression significantly, which was followed by increased deacetylation and inactivation of ATF6, resulting in a positive feedback loop for SIRT1 transcription associated with ATF6 binding to the SIRT1 promoter region. Conclusion: Taken together, these findings indicate that RSV supplementation improves hepatic steatosis by ameliorating the accumulation of LDs, and this might be partially mediated by a SIRT1/ATF6-dependent mechanism.

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“…However, their precise mechanism of action is not yet completely understood (Martin, Schoonjans, Lefebvre, Staels, & Auwerx, 1997;Schoonjans et al, 1995;Staels et al, 1998). Studies with diet-induced obese (DIO) mice models treated with this class of drugs showed important secondaries effects on preventing mass body gain, reducing fat stores, and improving insulin sensitivity as a result of decreased plasma fatty acid levels (Fernandes-Santos, Carneiro, de Souza Mendonca, Aguila, & Mandarim-de-Lacerda, 2009;Silva Veiga et al, 2017). Besides skeletal muscle and liver, recent findings suggest that PPARα agonists may also exert important effects on white adipose tissue (WAT) metabolism, playing a relevant role on their secondaries effects as well (Jeong & Yoon, 2009;Rachid et al, 2015).…”

mentioning

confidence: 99%

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

Frias

Rocha

Mendonça

et al. 2017

Journal Cellular Physiology

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The effect of fenofibrate on the metabolism of skeletal muscle and visceral white adipose tissue of diet-induced obese (DIO) mice was investigated. C57BL/6J male mice were fed either a control or high-fat diet for 8 weeks. Fenofibrate (50 mg/Kg BW, daily) was administered by oral gavage during the last two weeks of the experimental period. Insulin-stimulated glucose metabolism in soleus muscles, glucose tolerance test, insulin tolerance test, indirect calorimetry, lipolysis of visceral white adipose tissue, expression of miR-103-3p in adipose tissue, and miR-1a, miR-133a/b, miR-206, let7b-5p, miR-23b-3p, miR-29-3p, miR-143-3p in soleus muscle, genes related to glucose and fatty acid metabolism in adipose tissue and soleus muscle, and proteins (phospho-AMPKα2, Pgc1α, Cpt1b), intramuscular lipid staining, and activities of fatty acid oxidation enzymes in skeletal muscle were investigated. In DIO mice, fenofibrate prevented weight gain induced by HFD feeding by increasing energy expenditure; improved whole body glucose homeostasis, and in skeletal muscle, increased insulin dependent glucose uptake, miR-1a levels, reduced intramuscular lipid accumulation, and phospho-AMPKα2 levels. In visceral adipose tissue of obese mice, fenofibrate decreased basal lipolysis rate and visceral adipocytes hypertrophy, and induced the expression of Glut-4, Irs1, and Cav-1 mRNA and miR-103-3p suggesting a higher insulin sensitivity of the adipocytes. The evidence is presented herein that beneficial effects of fenofibrate on body weight, glucose homeostasis, and muscle metabolism might be related to its action in adipose tissue. Moreover, fenofibrate regulates miR-1a-3p in soleus and miR-103-3p in adipose tissue, suggesting these microRNAs might contribute to fenofibrate beneficial effects on metabolism.

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Anti-obesogenic effects of WY14643 (PPAR-alpha agonist): Hepatic mitochondrial enhancement and suppressed lipogenic pathway in diet-induced obese mice

Cited by 56 publications

References 55 publications

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

WITHDRAWN: An integrated analysis of microRNAs involved in fat deposition in different pig breeds

Resveratrol Ameliorates Lipid Droplet Accumulation in Liver Through a SIRT1/ ATF6-Dependent Mechanism

Fenofibrate reverses changes induced by high‐fat diet on metabolism in mice muscle and visceral adipocytes

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