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Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.
Kyriakou, Eleni; Schmidt, Stefanie; Dodd, Garron T; Pfuhlmann, Katrin; Simonds, Stephanie E; Lenhart, Dominik; Geerlof, Arie; Schriever, Sonja C; De Angelis, Meri; Schramm, Karl-Werner; Plettenburg, Oliver; Cowley, Michael A; Tiganis, Tony; Tschöp, Matthias H; Pfluger, Paul T; Sattler, Michael; Messias, Ana C.
Affiliation
  • Kyriakou E; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Schmidt S; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
  • Dodd GT; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Pfuhlmann K; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
  • Simonds SE; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology , Monash University , Victoria 3800 , Australia.
  • Lenhart D; Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Geerlof A; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Schriever SC; Division of Metabolic Diseases , Technische Universität München , 80333 Munich , Germany.
  • De Angelis M; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
  • Schramm KW; Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Physiology , Monash University , Victoria 3800 , Australia.
  • Plettenburg O; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Cowley MA; Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
  • Tiganis T; Institute of Medicinal Chemistry , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Tschöp MH; Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Pfluger PT; Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Sattler M; Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
  • Messias AC; German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
J Med Chem ; 61(24): 11144-11157, 2018 12 27.
Article de En | MEDLINE | ID: mdl-30525586
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.
Sujet(s)

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Triterpènes / Agents antiobésité / Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Obésité Type d'étude: Etiology_studies Limites: Animals Langue: En Journal: J Med Chem Sujet du journal: QUIMICA Année: 2018 Type de document: Article Pays d'affiliation: Allemagne Pays de publication: États-Unis d'Amérique

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Triterpènes / Agents antiobésité / Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Obésité Type d'étude: Etiology_studies Limites: Animals Langue: En Journal: J Med Chem Sujet du journal: QUIMICA Année: 2018 Type de document: Article Pays d'affiliation: Allemagne Pays de publication: États-Unis d'Amérique