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 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 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 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.

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.

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