Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1

Katrin Pfuhlmann, Sonja C. Schriever, Peter Baumann, Dhiraj G. Kabra, Luke Harrison, Sithandiwe E. Mazibuko-Mbeje, Raian E. Contreras, Eleni Kyriakou, Stephanie E. Simonds, Tony Tiganis, Michael A. Cowley, Stephen C. Woods, Martin Jastroch, Christoffer Clemmensen, Meri De Angelis, Karl Werner Schramm, Michael Sattler, Ana C. Messias, Matthias H. Tschöp, Paul T. Pfluger

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep ob mice respond with a decrease in food intake and body weight, adult Lep db and Lep ob mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.

Original languageEnglish
Pages (from-to)2456-2465
Number of pages10
JournalDiabetes
Volume67
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Cite this

Pfuhlmann, K., Schriever, S. C., Baumann, P., Kabra, D. G., Harrison, L., Mazibuko-Mbeje, S. E., ... Pfluger, P. T. (2018). Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. Diabetes, 67(11), 2456-2465. https://doi.org/10.2337/db18-0146
Pfuhlmann, Katrin ; Schriever, Sonja C. ; Baumann, Peter ; Kabra, Dhiraj G. ; Harrison, Luke ; Mazibuko-Mbeje, Sithandiwe E. ; Contreras, Raian E. ; Kyriakou, Eleni ; Simonds, Stephanie E. ; Tiganis, Tony ; Cowley, Michael A. ; Woods, Stephen C. ; Jastroch, Martin ; Clemmensen, Christoffer ; De Angelis, Meri ; Schramm, Karl Werner ; Sattler, Michael ; Messias, Ana C. ; Tschöp, Matthias H. ; Pfluger, Paul T. / Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. In: Diabetes. 2018 ; Vol. 67, No. 11. pp. 2456-2465.
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abstract = "Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep ob mice respond with a decrease in food intake and body weight, adult Lep db and Lep ob mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.",
author = "Katrin Pfuhlmann and Schriever, {Sonja C.} and Peter Baumann and Kabra, {Dhiraj G.} and Luke Harrison and Mazibuko-Mbeje, {Sithandiwe E.} and Contreras, {Raian E.} and Eleni Kyriakou and Simonds, {Stephanie E.} and Tony Tiganis and Cowley, {Michael A.} and Woods, {Stephen C.} and Martin Jastroch and Christoffer Clemmensen and {De Angelis}, Meri and Schramm, {Karl Werner} and Michael Sattler and Messias, {Ana C.} and Tsch{\"o}p, {Matthias H.} and Pfluger, {Paul T.}",
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Pfuhlmann, K, Schriever, SC, Baumann, P, Kabra, DG, Harrison, L, Mazibuko-Mbeje, SE, Contreras, RE, Kyriakou, E, Simonds, SE, Tiganis, T, Cowley, MA, Woods, SC, Jastroch, M, Clemmensen, C, De Angelis, M, Schramm, KW, Sattler, M, Messias, AC, Tschöp, MH & Pfluger, PT 2018, 'Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1', Diabetes, vol. 67, no. 11, pp. 2456-2465. https://doi.org/10.2337/db18-0146

Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. / Pfuhlmann, Katrin; Schriever, Sonja C.; Baumann, Peter; Kabra, Dhiraj G.; Harrison, Luke; Mazibuko-Mbeje, Sithandiwe E.; Contreras, Raian E.; Kyriakou, Eleni; Simonds, Stephanie E.; Tiganis, Tony; Cowley, Michael A.; Woods, Stephen C.; Jastroch, Martin; Clemmensen, Christoffer; De Angelis, Meri; Schramm, Karl Werner; Sattler, Michael; Messias, Ana C.; Tschöp, Matthias H.; Pfluger, Paul T.

In: Diabetes, Vol. 67, No. 11, 01.11.2018, p. 2456-2465.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Pfuhlmann, Katrin

AU - Schriever, Sonja C.

AU - Baumann, Peter

AU - Kabra, Dhiraj G.

AU - Harrison, Luke

AU - Mazibuko-Mbeje, Sithandiwe E.

AU - Contreras, Raian E.

AU - Kyriakou, Eleni

AU - Simonds, Stephanie E.

AU - Tiganis, Tony

AU - Cowley, Michael A.

AU - Woods, Stephen C.

AU - Jastroch, Martin

AU - Clemmensen, Christoffer

AU - De Angelis, Meri

AU - Schramm, Karl Werner

AU - Sattler, Michael

AU - Messias, Ana C.

AU - Tschöp, Matthias H.

AU - Pfluger, Paul T.

PY - 2018/11/1

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N2 - Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep ob mice respond with a decrease in food intake and body weight, adult Lep db and Lep ob mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.

AB - Celastrol, a plant-derived constituent of traditional Chinese medicine, has been proposed to offer significant potential as an antiobesity drug. However, the molecular mechanism for this activity is unknown. We show that the weight-lowering effects of celastrol are driven by decreased food consumption. Although young Lep ob mice respond with a decrease in food intake and body weight, adult Lep db and Lep ob mice are unresponsive to celastrol, suggesting that functional leptin signaling in adult mice is required to elicit celastrol's catabolic actions. Protein tyrosine phosphatase 1 (PTP1B), a leptin negative-feedback regulator, has been previously reported to be one of celastrol's targets. However, we found that global PTP1B knockout (KO) and wild-type (WT) mice have comparable weight loss and hypophagia when treated with celastrol. Increased levels of uncoupling protein 1 (UCP1) in subcutaneous white and brown adipose tissue suggest celastrol-induced thermogenesis as a further mechanism. However, diet-induced obese UCP1 WT and KO mice have comparable weight loss upon celastrol treatment, and celastrol treatment has no effect on energy expenditure under ambient housing or thermoneutral conditions. Overall, our results suggest that celastrol-induced weight loss is hypophagia driven and age-dependently mediated by functional leptin signaling. Our data encourage reconsideration of therapeutic antiobesity strategies built on leptin sensitization.

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Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE et al. Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1. Diabetes. 2018 Nov 1;67(11):2456-2465. https://doi.org/10.2337/db18-0146