Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

Michel Bernier; Dylan Harney; Yen Chin Koay; Antonio Diaz; Abhishek Singh; Devin Wahl; Tamara Pulpitel; Ahmed Ali; Vince Guiterrez; Sarah J. Mitchell; Eun Young Kim; John Mach; Nathan L. Price; Miguel A. Aon; David G. LeCouteur; Victoria C. Cogger; Carlos Fernandez-Hernando; John O’Sullivan; Mark Larance; Ana Maria Cuervo; Rafael de Cabo

doi:10.1038/s41514-020-0046-6

Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

Michel Bernier, Dylan Harney, Yen Chin Koay, Antonio Diaz, Abhishek Singh, Devin Wahl, Tamara Pulpitel, Ahmed Ali, Vince Guiterrez, Sarah J. Mitchell, Eun Young Kim, John Mach, Nathan L. Price, Miguel A. Aon, David G. LeCouteur, Victoria C. Cogger, Carlos Fernandez-Hernando, John O’Sullivan, Mark Larance, Ana Maria CuervoRafael de Cabo

Developmental & Molecular Biology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.

Original language	English (US)
Article number	8
Journal	npj Aging and Mechanisms of Disease
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41514-020-0046-6
State	Published - Dec 1 2020

ASJC Scopus subject areas

Aging
Geriatrics and Gerontology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41514-020-0046-6

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Bernier, M., Harney, D., Koay, Y. C., Diaz, A., Singh, A., Wahl, D., Pulpitel, T., Ali, A., Guiterrez, V., Mitchell, S. J., Kim, E. Y., Mach, J., Price, N. L., Aon, M. A., LeCouteur, D. G., Cogger, V. C., Fernandez-Hernando, C., O’Sullivan, J., Larance, M., ... de Cabo, R. (2020). Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome. npj Aging and Mechanisms of Disease, 6(1), [8]. https://doi.org/10.1038/s41514-020-0046-6

Bernier, M, Harney, D, Koay, YC, Diaz, A, Singh, A, Wahl, D, Pulpitel, T, Ali, A, Guiterrez, V, Mitchell, SJ, Kim, EY, Mach, J, Price, NL, Aon, MA, LeCouteur, DG, Cogger, VC, Fernandez-Hernando, C, O’Sullivan, J, Larance, M, Cuervo, AM & de Cabo, R 2020, 'Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome', npj Aging and Mechanisms of Disease, vol. 6, no. 1, 8. https://doi.org/10.1038/s41514-020-0046-6

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title = "Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome",

abstract = "There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.",

author = "Michel Bernier and Dylan Harney and Koay, {Yen Chin} and Antonio Diaz and Abhishek Singh and Devin Wahl and Tamara Pulpitel and Ahmed Ali and Vince Guiterrez and Mitchell, {Sarah J.} and Kim, {Eun Young} and John Mach and Price, {Nathan L.} and Aon, {Miguel A.} and LeCouteur, {David G.} and Cogger, {Victoria C.} and Carlos Fernandez-Hernando and John O{\textquoteright}Sullivan and Mark Larance and Cuervo, {Ana Maria} and {de Cabo}, Rafael",

note = "Funding Information: This work was supported by funding from the Intramural Research Program of the National Institute on Aging/NIH, NIH/NIA grants AG031782 and AG038072 (A.M.C.), and NIH Award R35HL135820 (C.F.-H.). M.L. is a Cancer Institute New South Wales Future Research Leader Fellow (15/FRL/1-06 A). This work was supported by grants from the NHMRC (APP1120475). We thank SydneyMS for providing the mass spectrometry instrumentation used in this study. E.Y.K. was supported by a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. The mouse liver samples were microarrayed and analyzed by the Gene Expression and Genomics Core at the National Institutes of Aging Intramural Research Program (Elin Lehrmann performed sample QC, labeling, arraying, and data extraction plus GEO submission, whereas Yongqing Zhang performed the bioinfor-matic data analysis for these samples). We are grateful to the Comparative Medicine Section of the NIA, NIH for their exceptional animal care, and particularly Dawn Nines, Dawn Boyer, Kristan Gavin, and Kevin Jenkins for their assistance with the study. The contribution of Marc Raley at NIA Visual Media Service is acknowledged. Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

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doi = "10.1038/s41514-020-0046-6",

language = "English (US)",

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T1 - Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

AU - Bernier, Michel

AU - Harney, Dylan

AU - Koay, Yen Chin

AU - Diaz, Antonio

AU - Singh, Abhishek

AU - Wahl, Devin

AU - Pulpitel, Tamara

AU - Ali, Ahmed

AU - Guiterrez, Vince

AU - Mitchell, Sarah J.

AU - Kim, Eun Young

AU - Mach, John

AU - Price, Nathan L.

AU - Aon, Miguel A.

AU - LeCouteur, David G.

AU - Cogger, Victoria C.

AU - Fernandez-Hernando, Carlos

AU - O’Sullivan, John

AU - Larance, Mark

AU - Cuervo, Ana Maria

AU - de Cabo, Rafael

N1 - Funding Information: This work was supported by funding from the Intramural Research Program of the National Institute on Aging/NIH, NIH/NIA grants AG031782 and AG038072 (A.M.C.), and NIH Award R35HL135820 (C.F.-H.). M.L. is a Cancer Institute New South Wales Future Research Leader Fellow (15/FRL/1-06 A). This work was supported by grants from the NHMRC (APP1120475). We thank SydneyMS for providing the mass spectrometry instrumentation used in this study. E.Y.K. was supported by a grant from the KRIBB Research Initiative Program (Korean Biomedical Scientist Fellowship Program), Korea Research Institute of Bioscience and Biotechnology, Republic of Korea. The mouse liver samples were microarrayed and analyzed by the Gene Expression and Genomics Core at the National Institutes of Aging Intramural Research Program (Elin Lehrmann performed sample QC, labeling, arraying, and data extraction plus GEO submission, whereas Yongqing Zhang performed the bioinfor-matic data analysis for these samples). We are grateful to the Comparative Medicine Section of the NIA, NIH for their exceptional animal care, and particularly Dawn Nines, Dawn Boyer, Kristan Gavin, and Kevin Jenkins for their assistance with the study. The contribution of Marc Raley at NIA Visual Media Service is acknowledged. Publisher Copyright: © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

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AB - There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.

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Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome

Abstract

ASJC Scopus subject areas

UN SDGs

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