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Diabetes. 2018 Nov;67(11):2456-2465. doi: 10.2337/db18-0146. Epub 2018 Aug 28.

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

Author information

1
Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, Neuherberg, Germany.
2
Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany.
3
Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
4
German Center for Diabetes Research (DZD), Neuherberg, Germany.
5
Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany.
6
Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa.
7
Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
8
Biomolecular Nuclear Magnetic Resonance and Center for Integrated Protein Science Munich at Department Chemie, Technische Universität München, Garching, Germany.
9
Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia.
10
Department of Physiology, Monash University, Melbourne, Victoria, Australia.
11
Psychiatry and Behavioral Neuroscience, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH.
12
Molecular EXposomics, Helmholtz Zentrum München, Neuherberg, Germany.
13
Research Unit Neurobiology of Diabetes, Helmholtz Zentrum München, Neuherberg, Germany paul.pfluger@helmholtz-muenchen.de.

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.

Comment in

PMID:
30158241
DOI:
10.2337/db18-0146
[Indexed for MEDLINE]
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