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 Tschöp; Paul T Pfluger; Michael Sattler; Ana C Messias

doi:10.1021/acs.jmedchem.8b01224

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

J Med Chem. 2018 Dec 27;61(24):11144-11157. doi: 10.1021/acs.jmedchem.8b01224. Epub 2018 Dec 7.

Authors

Eleni Kyriakou^{1

2}, Stefanie Schmidt^{1

2}, Garron T Dodd³, Katrin Pfuhlmann^{4

5

6

7}, Stephanie E Simonds⁸, Dominik Lenhart^{1

2

9}, Arie Geerlof¹, Sonja C Schriever^{4

5

7}, Meri De Angelis¹⁰, Karl-Werner Schramm¹⁰, Oliver Plettenburg^{9

11}, Michael A Cowley⁸, Tony Tiganis^{3

12}, Matthias H Tschöp^{5

6

7}, Paul T Pfluger^{4

5

7}, Michael Sattler^{1

2}, Ana C Messias^{1

2}

Affiliations

¹ Institute of Structural Biology , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
² Biomolecular NMR and Center for Integrated Protein Science Munich at Department of Chemistry , Technical University of Munich , 85747 Garching , Germany.
³ Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Biochemistry and Molecular Biology , Monash University , Victoria 3800 , Australia.
⁴ Research Unit Neurobiology of Diabetes , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
⁵ Institute for Diabetes and Obesity , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
⁶ Division of Metabolic Diseases , Technische Universität München , 80333 Munich , Germany.
⁷ German Center for Diabetes Research (DZD) , 85764 Neuherberg , Germany.
⁸ Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, and Department of Physiology , Monash University , Victoria 3800 , Australia.
⁹ Institute of Medicinal Chemistry , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
¹⁰ Molecular EXposomics , Helmholtz Zentrum München , 85764 Neuherberg , Germany.
¹¹ Institute of Organic Chemistry , Leibniz Universität Hannover , 30167 Hannover , Germany.
¹² Peter MacCallum Cancer Centre , Melbourne , Victoria 3000 , Australia.

PMID: 30525586
DOI: 10.1021/acs.jmedchem.8b01224

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site
Animals
Anti-Obesity Agents / metabolism
Anti-Obesity Agents / pharmacology*
Catalytic Domain
Diet, High-Fat / adverse effects
Hypothalamus / drug effects
Hypothalamus / metabolism
Magnetic Resonance Spectroscopy
Male
Mice, Transgenic
Obesity / drug therapy*
Obesity / etiology
Pentacyclic Triterpenes
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / antagonists & inhibitors*
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 / antagonists & inhibitors*
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
Triterpenes / pharmacology*
Weight Loss / drug effects

Substances

Anti-Obesity Agents
Pentacyclic Triterpenes
Triterpenes
Protein Tyrosine Phosphatase, Non-Receptor Type 1
Protein Tyrosine Phosphatase, Non-Receptor Type 2
Ptpn1 protein, mouse
celastrol