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

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3 Citations (Scopus)

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.

Original languageEnglish
Number of pages14
JournalJournal of Medicinal Chemistry
Volume61
Issue number24
DOIs
Publication statusPublished - 7 Dec 2018

Cite this

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. / Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 24.
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title = "Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus",
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.",
author = "Eleni Kyriakou and Stefanie Schmidt and Dodd, {Garron T.} and Katrin Pfuhlmann and Simonds, {Stephanie E.} and Dominik Lenhart and Arie Geerlof and Schriever, {Sonja C.} and {De Angelis}, Meri and Schramm, {Karl Werner} and Oliver Plettenburg and Cowley, {Michael A.} and Tony Tiganis and Tsch{\"o}p, {Matthias H.} and Pfluger, {Paul T.} and Michael Sattler and Messias, {Ana C.}",
year = "2018",
month = "12",
day = "7",
doi = "10.1021/acs.jmedchem.8b01224",
language = "English",
volume = "61",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "24",

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Kyriakou, E, Schmidt, S, Dodd, GT, Pfuhlmann, K, Simonds, SE, Lenhart, D, Geerlof, A, Schriever, SC, De Angelis, M, Schramm, KW, Plettenburg, O, Cowley, MA, Tiganis, T, Tschöp, MH, Pfluger, PT, Sattler, M & Messias, AC 2018, 'Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus', Journal of Medicinal Chemistry, vol. 61, no. 24. https://doi.org/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. / 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.

In: Journal of Medicinal Chemistry, Vol. 61, No. 24, 07.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus

AU - Kyriakou, Eleni

AU - Schmidt, Stefanie

AU - Dodd, Garron T.

AU - Pfuhlmann, Katrin

AU - Simonds, Stephanie E.

AU - Lenhart, Dominik

AU - Geerlof, Arie

AU - Schriever, Sonja C.

AU - De Angelis, Meri

AU - Schramm, Karl Werner

AU - Plettenburg, Oliver

AU - Cowley, Michael A.

AU - Tiganis, Tony

AU - Tschöp, Matthias H.

AU - Pfluger, Paul T.

AU - Sattler, Michael

AU - Messias, Ana C.

PY - 2018/12/7

Y1 - 2018/12/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85058573385&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01224

DO - 10.1021/acs.jmedchem.8b01224

M3 - Article

VL - 61

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 24

ER -