| A nonthiazolidinedione peroxisome proliferator-activated receptor α/γ dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db mice. | |
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MedLine Citation:
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PMID: 20724462 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Activation of peroxisome proliferator-activated receptors (PPARs) have been implicated in the treatment of metabolic disorders with different mechanisms; PPARα agonists promote fatty acid oxidation and reduce hyperlipidemia, whereas PPARγ agonists regulate lipid redistribution from visceral fat to subcutaneous fat and enhance insulin sensitivity. To achieve combined benefits from activated PPARs on lipid metabolism and insulin sensitivity, a number of PPARα/γ dual agonists have been developed. However, several adverse effects such as weight gain and organ failure of PPARα/γ dual agonists have been reported. By use of virtual ligand screening, we identified and characterized a novel PPARα/γ dual agonist, (R)-1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid (CG301360), exhibiting the improvement in insulin sensitivity and lipid metabolism. CG301360 selectively stimulated transcriptional activities of PPARα and PPARγ and induced expression of their target genes in a PPARα- and PPARγ-dependent manner. In cultured cells, CG301360 enhanced fatty acid oxidation and glucose uptake and it reduced pro-inflammatory gene expression. In db/db mice, CG301360 also restored insulin sensitivity and lipid homeostasis. Collectively, these data suggest that CG301360 would be a novel PPARα/γ agonist, which might be a potential lead compound to develop against insulin resistance and hyperlipidemia. |
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Authors:
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Hyun Woo Jeong; Joo-Won Lee; Woo Sik Kim; Sung Sik Choe; Hyun Jung Shin; Gha Young Lee; Dongkyu Shin; Jun Hee Lee; Eun Bok Choi; Hyun Kyu Lee; Gyu Hwan Yon; Bongjun Cho; Hye Ryung Kim; Sung Hee Choi; Young Sun Chung; Seung Bum Park; Heekyoung Chung; Seonggu Ro; Jae Bum Kim |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-08-19 |
Journal Detail:
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Title: Molecular pharmacology Volume: 78 ISSN: 1521-0111 ISO Abbreviation: Mol. Pharmacol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-20 Completed Date: 2010-12-07 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0035623 Medline TA: Mol Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 877-85 Citation Subset: IM |
Affiliation:
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School of Biological Sciences, Seoul National University, Kwanak-Gu, Seoul, Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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drug effects,
metabolism Animals Cells, Cultured Cyclooxygenase 2 / biosynthesis Cytokines / biosynthesis Fatty Acids / metabolism Gene Expression Regulation / drug effects Glucose / metabolism Insulin Resistance* Lipid Metabolism / drug effects* Macrophages / drug effects, metabolism Matrix Metalloproteinase 9 / biosynthesis Mice Mice, Obese Oxazoles / pharmacology* Oxidation-Reduction PPAR alpha / agonists*, physiology PPAR delta / agonists*, physiology Pipecolic Acids / pharmacology* Stereoisomerism Transcription, Genetic |
| Chemical | |
Reg. No./Substance:
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0/1-(4-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2-carboxylic acid; 0/Cytokines; 0/Fatty Acids; 0/Oxazoles; 0/PPAR alpha; 0/PPAR delta; 0/Pipecolic Acids; 50-99-7/Glucose; EC 1.14.99.1/Cyclooxygenase 2; EC 3.4.24.35/Matrix Metalloproteinase 9 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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