Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus
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 Tschoep, Paul T Pfluger, Michael Sattler, Ana C Messias
JOURNAL OF MEDICINAL CHEMISTRY | AMER CHEMICAL SOC | Published : 2018
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 i..View full abstract
We thank Astrid Lauxen for technical assistance, Florian Ruehrnoessl for recording and analysing the MALDI-TOF spectra, Fjolla Ismajli and Thomas Welte from Dynamic Biosensors GmbH for switchSENSE measurements with the PTP1B-celastrol, and Dr. Monica Campillos Gonzalez for surveying celastrol target literature. This work was supported in part by the Helmholtz Portofolio Program "Metabolic Dysfunction" (M.S., M.H.T.), by an IMF Diabetes Portfolio grant (A.C.M., M.S.), by the Alexander von Humboldt Foundation (M.H.T.), by the Helmholtz Alliance ICEMED-Imaging and Curing Environmental Metabolic Diseases (S.C.S., M.H.T.), by the NHMRC Australia (M.A.C., S.E.S., and T.T.) and National Heart Foundation of Australia (S.E.S.), by the Helmholtz-Israel-Cooperation in Personalized Medicine (P.P.), by the Helmholtz Initiative for Personalized Medicine (iMed; M.H.T.), and through the Initiative and Networking Fund of the Helmholtz Association.