Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus

verfasst von

Eleni Kyriakou, Stefanie Schmidt, Garron T. Dodd, Katrin Pfuhlmann, Stephanie E. Simonds, Dominik Lenhart, Arie Geerlof, Sonja C. Schriever, Meri De Angelis, Karl Werner Schramm, Oliver Plettenburg, Michael A. Cowley, Tony Tiganis, Matthias H. Tschöp, Paul T. Pfluger, Michael Sattler, Ana C. Messias

Abstract

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.

Organisationseinheit(en)

Institut für Organische Chemie

Externe Organisation(en)

Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Monash University
Technische Universität München (TUM)
Deutsches Zentrum für Diabetesforschung e.V. (DZD)
Peter Maccallum Cancer Centre

Typ

Artikel

Journal

Journal of Medicinal Chemistry

Band

61

Seiten

11144-11157

Anzahl der Seiten

14

ISSN

0022-2623

Publikationsdatum

07.12.2018

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Molekularmedizin, Wirkstoffforschung

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1021/acs.jmedchem.8b01224 (Zugang: Geschlossen)