scholarly journals 8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet-Induced Obese Mice

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Hidetoshi Yamada ◽  
Sayaka Kikuchi ◽  
Mayuka Hakozaki ◽  
Kaori Motodate ◽  
Nozomi Nagahora ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Ppar Ligand ◽  
Obesity In Mice ◽  
Ligand Activity

PPARs regulate the expression of genes involved in lipid homeostasis. PPARs serve as molecular sensors of fatty acids, and their activation can act against obesity and metabolic syndromes. 8-Hydroxyeicosapentaenoic acid (8-HEPE) acts as a PPAR ligand and has higher activity than EPA. However, to date, the PPAR ligand activity of 8-HEPE has only been demonstratedin vitro. Here, we investigated its ligand activityin vivoby examining the effect of 8-HEPE treatment on high fat diet-induced obesity in mice. After the 4-week treatment period, the levels of plasma and hepatic triglycerides in the 8-HEPE-fed mice were significantly lower than those in the HFD-fed mice. The expression of genes regulated by PPARαwas significantly increased in 8-HEPE-fed mice compared to those that received only HFD. Additionally, the level of hepatic palmitic acid in 8-HEPE-fed mice was significantly lower than in HFD-fed mice. These results suggested that intake of 8-HEPE induced PPARαactivation and increased catabolism of lipids in the liver. We found no significant differences between EPA-fed mice and HFD-fed mice. We demonstrated that 8-HEPE has a larger positive effect on metabolic syndrome than EPA and that 8-HEPE acts by inducing PPARαactivation in the liver.

scholarly journals Curcumin improves glycolipid metabolism through regulating peroxisome proliferator activated receptor γ signalling pathway in high-fat diet-induced obese mice and 3T3-L1 adipocytes

2017 ◽  
Vol 4 (11) ◽  
pp. 170917 ◽  
Author(s):  
Yanyun Pan ◽  
Dandan Zhao ◽  
Na Yu ◽  
Tian An ◽  
Jianan Miao ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Fasting Blood Glucose ◽  
Signalling Pathway ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glycolipid Metabolism

Curcumin is an active component derived from Curcuma longa L. which is a traditional Chinese medicine that is widely used for treating metabolic diseases through regulating different molecular pathways. Here, in this study, we aimed to comprehensively investigate the effects of curcumin on glycolipid metabolism in vivo and in vitro and then determine the underlying mechanism. Male C57BL/6 J obese mice and 3T3-L1 adipocytes were used for in vivo and in vitro study, respectively. Our results demonstrated that treatment with curcumin for eight weeks decreased body weight, fat mass and serum lipid profiles. Meanwhile, it lowered fasting blood glucose and increased the insulin sensitivity in high-fat diet-induced obese mice. In addition, curcumin stimulated lipolysis and improved glycolipid metabolism through upregulating the expressions of adipose triglyceride lipase and hormone-sensitive lipase, peroxisome proliferator activated receptor γ/α (PPARγ/α) and CCAAT/enhancer binding proteinα (C/EBPα) in adipose tissue of the mice. In differentiated 3T3-L1 cells, curcumin reduced glycerol release and increased glucose uptake via upregulating PPARγ and C/EBPα. We concluded that curcumin has the potential to improve glycolipid metabolism disorders caused by obesity through regulating PPARγ signalling pathway.

scholarly journals Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yang Zhang ◽  
Gerd Bobe ◽  
Cristobal L Miranda ◽  
Malcolm B Lowry ◽  
Victor L Hsu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
High Fat Diet ◽  
Caloric Intake ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Competitive Binding Assay ◽  
Docking Simulations ◽  
Synthetic Derivative

We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8–10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.

scholarly journals Liver-specific knockdown of long-chain acyl-CoA synthetase 4 reveals its key role in VLDL-TG metabolism and phospholipid synthesis in mice fed a high-fat diet

2019 ◽  
Vol 316 (5) ◽  
pp. E880-E894 ◽  
Author(s):  
Amar B. Singh ◽  
Chin Fung K. Kan ◽  
Fredric B. Kraemer ◽  
Raymond A. Sobel ◽  
Jingwen Liu
Keyword(s):  
High Fat Diet ◽  
Plasma Cholesterol ◽  
Peroxisome Proliferator ◽  
Synthetase Activity ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Chain Acyl ◽  
Long Chain

Long-chain acyl-CoA synthetase 4 (ACSL4) has a unique substrate specificity for arachidonic acid. Hepatic ACSL4 is coregulated with the phospholipid (PL)-remodeling enzyme lysophosphatidylcholine (LPC) acyltransferase 3 by peroxisome proliferator-activated receptor δ to modulate the plasma triglyceride (TG) metabolism. In this study, we investigated the acute effects of hepatic ACSL4 deficiency on lipid metabolism in adult mice fed a high-fat diet (HFD). Adenovirus-mediated expression of a mouse ACSL4 shRNA (Ad-shAcsl4) in the liver of HFD-fed mice led to a 43% reduction of hepatic arachidonoyl-CoA synthetase activity and a 53% decrease in ACSL4 protein levels compared with mice receiving control adenovirus (Ad-shLacZ). Attenuated ACSL4 expression resulted in a substantial decrease in circulating VLDL-TG levels without affecting plasma cholesterol. Lipidomics profiling revealed that knocking down ACSL4 altered liver PL compositions, with the greatest impact on accumulation of abundant LPC species (LPC 16:0 and LPC 18:0) and lysophosphatidylethanolamine (LPE) species (LPE 16:0 and LPE 18:0). In addition, fasting glucose and insulin levels were higher in Ad-shAcsl4-transduced mice versus control (Ad-shLacZ). Glucose tolerance testing further indicated an insulin-resistant phenotype upon knockdown of ACSL4. These results provide the first in vivo evidence that ACSL4 plays a role in plasma TG and glucose metabolism and hepatic PL synthesis of hyperlipidemic mice.

Antagonism of peroxisome proliferator-activated receptor γ prevents high-fat diet-induced obesity in vivo

2006 ◽  
Vol 72 (1) ◽  
pp. 42-52 ◽  
Author(s):  
Ryosuke Nakano ◽  
Eiji Kurosaki ◽  
Shigeru Yoshida ◽  
Masanori Yokono ◽  
Akiyoshi Shimaya ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

scholarly journals Effect ofLactobacillus plantarumStrain K21 on High-Fat Diet-Fed Obese Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Chien-Chen Wu ◽  
Wei-Lien Weng ◽  
Wen-Lin Lai ◽  
Hui-Ping Tsai ◽  
Wei-Hsien Liu ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Body Weight Gain ◽  
Normal Diet ◽  
Peroxisome Proliferator ◽  
Bacterial Strains ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hepatic Expression ◽  
Beneficial Effects

Recent studies have demonstrated beneficial effects of specific probiotics on alleviating obesity-related disorders. Here we aimed to identify probiotics with potential antiobesity activity among 88 lactic acid bacterial strains viain vitroscreening assays, and aLactobacillus plantarumstrain K21 was found to harbor abilities required for hydrolyzing bile salt, reducing cholesterol, and inhibiting the accumulation of lipid in 3T3-L1 preadipocytes. Furthermore, effects of K21 on diet-induced obese (DIO) mice were examined. Male C57Bl/6J mice received a normal diet, high-fat diet (HFD), or HFD with K21 administration (109 CFU in 0.2 mL PBS/day) for eight weeks. Supplementation of K21, but not placebo, appeared to alleviate body weight gain and epididymal fat mass accumulation, reduce plasma leptin levels, decrease cholesterol and triglyceride levels, and mitigate liver damage in DIO mice. Moreover, the hepatic expression of peroxisome proliferator-activated receptor-γ(PPAR-γ) related to adipogenesis was significantly downregulated in DIO mice by K21 intervention. We also found that K21 supplementation strengthens intestinal permeability and modulates the amount ofLactobacillusspp.,Bifidobacteriumspp., andClostridium perfringensin the cecal contents of DIO mice. In conclusion, our results suggest that dietary intake of K21 protects against the onset of HFD-induced obesity through multiple mechanisms of action.

scholarly journals Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator-activated receptor-α function in vivo

2014 ◽  
Vol 306 (7) ◽  
pp. E824-E837 ◽  
Author(s):  
Jessica A. Bonzo ◽  
Chad Brocker ◽  
Changtao Jiang ◽  
Rui-Hong Wang ◽  
Chu-Xia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Target Genes ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor-α (PPARα) mediates metabolic remodeling, resulting in enhanced mitochondrial and peroxisomal β-oxidation of fatty acids. In addition to the physiological stimuli of fasting and high-fat diet, PPARα is activated by the fibrate class of drugs for the treatment of dyslipidemia. Sirtuin 1 (SIRT1), an important regulator of energy homeostasis, was downregulated in fibrate-treated wild-type mice, suggesting PPARα regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPARα functionality in vivo was assessed in hepatocyte-specific knockout mice that lack the deacetylase domain of SIRT1 ( Sirt1 ΔLiv). Knockout mice were treated with fibrates or fasted for 24 h to activate PPARα. Basal expression of the PPARα target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1 ΔLiv mice compared with wild-type mice. However, no difference was observed between wild-type and Sirt1 ΔLiv mice in either fasting- or fibrate-mediated induction of PPARα target genes. Similar to the initial results, there was no difference in fibrate-activated PPARα gene induction. To assess the relationship between SIRT1 and PPARα in a pathophysiological setting, Sirt1 ΔLiv mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1 ΔLiv mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1 ΔLiv mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPARα target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPARα activity.

scholarly journals Loss of Ron receptor signaling leads to reduced obesity, diabetic phenotypes and hepatic steatosis in response to high-fat diet in mice

2015 ◽  
Vol 308 (7) ◽  
pp. E562-E572 ◽  
Author(s):  
William D. Stuart ◽  
Nicholas E. Brown ◽  
Andrew M. Paluch ◽  
Susan E. Waltz
Keyword(s):  
Tyrosine Kinase ◽  
High Fat Diet ◽  
Inflammatory Responses ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ron Receptor ◽  
Membrane Spanning

The Ron receptor tyrosine kinase is a heterodimeric, membrane-spanning glycoprotein that participates in divergent processes, including proliferation, motility, and modulation of inflammatory responses. We observed male C57BL/6 mice with a global deletion of the Ron tyrosine kinase signaling domain (TK−/−) to be leaner compared with control (TK+/+) mice under a standard diet. When fed a high-fat diet (HFD), TK−/− mice gained 50% less weight and were more insulin sensitive and glucose tolerant than controls. Livers from HFD TK−/− mice were considerably less steatotic and weighed significantly less than TK+/+ livers. Serum cytokine levels of HFD TK−/− mice were also significantly altered compared with TK+/+ mice. Fewer and smaller adipocytes were present in the TK−/− mice on both control and HFD and were accompanied by diminished adiponectin and peroxisome proliferator-activated receptor-γ expression. In vitro adipogenesis experiments suggested reduced differentiation in TK−/− embryonic fibroblasts (MEFs) that was rescued by Ron reconstitution. Likewise, signal transducer and activator of transcription (STAT)-3 phosphorylation was diminished in TK−/− MEFs but was increased after Ron reconstitution. The adipogenic inhibitors, preadipocyte factor 1 and Sox9, were elevated in TK−/− MEFs and increased in both groups after STAT3 silencing. In total, these studies document a previously unknown function for the Ron receptor in mediating HFD-induced obesity and metabolic dysregulation.

Identification of hepatic transcriptional changes in insulin-resistant rats treated with peroxisome proliferator activated receptor-alpha agonists

2003 ◽  
Vol 30 (3) ◽  
pp. 317-329 ◽  
Author(s):  
KS Frederiksen ◽  
EM Wulf ◽  
K Wassermann ◽  
P Sauerberg ◽  
J Fleckner
Keyword(s):  
Insulin Resistance ◽  
Tyrosine Phosphatase ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
High Fat ◽  
Transcriptional Responses ◽  
Ppar Alpha ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator activated receptor (PPAR)-alpha controls the expression of multiple genes involved in lipid metabolism, and activators of PPAR-alpha, such as fibrates, are commonly used drugs in the treatment of hypertriglyceridemia and other dyslipidemic states. Recent data have also suggested a role for PPAR-alpha in insulin resistance and glucose homeostasis. In the present study, we have assessed the transcriptional and physiological responses to PPAR-alpha activation in a diet-induced rat model of insulin resistance. The two PPAR-alpha activators, fenofibrate and Wy-14643, were dosed at different concentrations in high-fat fed Sprague-Dawley rats, and the transcriptional responses were examined in liver using cDNA microarrays. In these analyses, 98 genes were identified as being regulated by both compounds. From this pool of genes, 27 correlated to the observed effect on plasma insulin, including PPAR-alpha itself and the leukocyte antigen-related protein tyrosine phosphatase (PTP-LAR). PTP-LAR was downregulated by both compounds, and showed upregulation as a result of the high-fat feeding. This regulation was also observed at the protein level. Furthermore, downregulation of PTP-LAR by fenofibric acid was demonstrated in rat FaO hepatoma cells in vitro, indicating that the observed regulation of PTP-LAR by fenofibrate and Wy-14643 in vivo is mediated as a direct effect of the PPAR agonists on the hepatocytes. PTP-LAR is one of the first genes involved in insulin receptor signaling to be shown to be regulated by PPAR-alpha agonists. These data suggest that factors apart from skeletal muscle lipid supply may influence PPAR-alpha-mediated amelioration of insulin resistance.

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