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Tytuł:
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Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.
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Autorzy:
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Kyriakou E; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
Schmidt S; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
Dodd GT; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology , Monash University , Victoria 3800 , Australia.
Pfuhlmann K; Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Division of Metabolic Diseases , Technische Universität München , 80333 Munich , Germany.; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
Simonds SE; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Physiology , Monash University , Victoria 3800 , Australia.
Lenhart D; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.; Institute of Medicinal Chemistry , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
Geerlof A; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
Schriever SC; Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
De Angelis M; Molecular EXposomics , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
Schramm KW; Molecular EXposomics , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
Plettenburg O; Institute of Medicinal Chemistry , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Institute of Organic Chemistry , Leibniz Universität Hannover , 30167 Hannover , Germany.
Cowley MA; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Physiology , Monash University , Victoria 3800 , Australia.
Tiganis T; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology , Monash University , Victoria 3800 , Australia.; Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia.
Tschöp MH; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Division of Metabolic Diseases , Technische Universität München , 80333 Munich , Germany.; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
Pfluger PT; Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
Sattler M; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
Messias AC; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
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Źródło:
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Journal of medicinal chemistry [J Med Chem] 2018 Dec 27; Vol. 61 (24), pp. 11144-11157. Date of Electronic Publication: 2018 Dec 07.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
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MeSH Terms:
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Anti-Obesity Agents/*pharmacology
Obesity/*drug therapy
Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists & inhibitors
Protein Tyrosine Phosphatase, Non-Receptor Type 2/*antagonists & inhibitors
Triterpenes/*pharmacology
Allosteric Site ; Animals ; Anti-Obesity Agents/metabolism ; Catalytic Domain ; Diet, High-Fat/adverse effects ; Hypothalamus/drug effects ; Hypothalamus/metabolism ; Magnetic Resonance Spectroscopy ; Male ; Mice, Transgenic ; Obesity/etiology ; Pentacyclic Triterpenes ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 1/metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 2/chemistry ; Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 2/metabolism ; Structure-Activity Relationship ; Triterpenes/chemistry ; Triterpenes/metabolism ; Weight Loss/drug effects
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Substance Nomenclature:
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0 (Anti-Obesity Agents)
0 (Pentacyclic Triterpenes)
0 (Triterpenes)
EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1)
EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 2)
EC 3.1.3.48 (Ptpn1 protein, mouse)
L8GG98663L (celastrol)
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Entry Date(s):
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Date Created: 20181212 Date Completed: 20191028 Latest Revision: 20211204
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Update Code:
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20240105
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DOI:
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10.1021/acs.jmedchem.8b01224
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PMID:
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30525586
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Celastrol is a natural pentacyclic triterpene used in traditional Chinese medicine with significant weight-lowering effects. Celastrol-administered mice at 100 μg/kg decrease food consumption and body weight via a leptin-dependent mechanism, yet its molecular targets in this pathway remain elusive. Here, we demonstrate in vivo that celastrol-induced weight loss is largely mediated by the inhibition of leptin negative regulators protein tyrosine phosphatase (PTP) 1B (PTP1B) and T-cell PTP (TCPTP) in the arcuate nucleus (ARC) of the hypothalamus. We show in vitro that celastrol binds reversibly and inhibits noncompetitively PTP1B and TCPTP. NMR data map the binding site to an allosteric site in the catalytic domain that is in proximity of the active site. By using a panel of PTPs implicated in hypothalamic leptin signaling, we show that celastrol additionally inhibited PTEN and SHP2 but had no activity toward other phosphatases of the PTP family. These results suggest that PTP1B and TCPTP in the ARC are essential for celastrol's weight lowering effects in adult obese mice.
