Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation

Rami Al Batran; Keshav Gopal; Megan E. Capozzi; Jadin J. Chahade; Bruno Saleme; S. Amirhossein Tabatabaei-Dakhili; Amanda A. Greenwell; Jingjing Niu; Malak Almutairi; Nikole J. Byrne; Grant Masson; Ryekjang Kim; Farah Eaton; Erin E. Mulvihill; Léa Garneau; Andrea R. Masters; Zeruesenay Desta; Carlos A. Velázquez-Martínez; Céline Aguer; Peter A. Crawford; Gopinath Sutendra; Jonathan E. Campbell; Jason R.B. Dyck; John R. Ussher

doi:10.1016/j.cmet.2020.03.017

Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation

Rami Al Batran, Keshav Gopal, Megan E. Capozzi, Jadin J. Chahade, Bruno Saleme, S. Amirhossein Tabatabaei-Dakhili, Amanda A. Greenwell, Jingjing Niu, Malak Almutairi, Nikole J. Byrne, Grant Masson, Ryekjang Kim, Farah Eaton, Erin E. Mulvihill, Léa Garneau, Andrea R. Masters, Zeruesenay Desta, Carlos A. Velázquez-Martínez, Céline Aguer, Peter A. CrawfordGopinath Sutendra, Jonathan E. Campbell, Jason R.B. Dyck, John R. Ussher

Molecular Medicine

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

21 Scopus citations

Abstract

Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

Original language	English (US)
Pages (from-to)	909-919.e8
Journal	Cell Metabolism
Volume	31
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2020.03.017
State	Published - May 5 2020

Bibliographical note

Funding Information:
The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709. We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant (5U2C-DK093000). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C. an Allocation Jeune Chercheur from the Société Francophone du Diabéte to C.A. and a Project Grant and Foundation Grant to G.S. and J.R.B.D. respectively, from the CIHR. Conceptualization, R.A. and J.R.U.; Investigation, R.A. K.G. M.E.C. J.J.C. B.S. S.A.T.D. A.A.G. J.N. M.A. N.J.B. G.M. R.K. F.E. E.E.M. L.G. A.R.M. and C.A.; Formal Analysis and Visualization, R.A. and K.G.; Writing – Original Draft, R.A. and J.R.U.; Writing – Review & Editing, R.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Funding Acquisition and Project Administration, J.R.U.; Resources, Z.D. C.V. C.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Supervision, J.R.U. J.R.U. takes full responsibility for the data within this paper. The University of Alberta has filed a patent application regarding the subject matter of this article.

Funding Information:
The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709 . We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant ( 5U2C-DK093000 ). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C., an Allocation Jeune Chercheur from the Société Francophone du Diabéte to C.A., and a Project Grant and Foundation Grant to G.S. and J.R.B.D., respectively, from the CIHR.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

glycemia
insulin resistance
ketone bodies
ketone body oxidation
obesity
pimozide
type 2 diabetes

UN SDGs

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

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10.1016/j.cmet.2020.03.017

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Al Batran, R., Gopal, K., Capozzi, M. E., Chahade, J. J., Saleme, B., Tabatabaei-Dakhili, S. A., Greenwell, A. A., Niu, J., Almutairi, M., Byrne, N. J., Masson, G., Kim, R., Eaton, F., Mulvihill, E. E., Garneau, L., Masters, A. R., Desta, Z., Velázquez-Martínez, C. A., Aguer, C., ... Ussher, J. R. (2020). Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation. Cell Metabolism, 31(5), 909-919.e8. https://doi.org/10.1016/j.cmet.2020.03.017

Al Batran, R, Gopal, K, Capozzi, ME, Chahade, JJ, Saleme, B, Tabatabaei-Dakhili, SA, Greenwell, AA, Niu, J, Almutairi, M, Byrne, NJ, Masson, G, Kim, R, Eaton, F, Mulvihill, EE, Garneau, L, Masters, AR, Desta, Z, Velázquez-Martínez, CA, Aguer, C, Crawford, PA, Sutendra, G, Campbell, JE, Dyck, JRB & Ussher, JR 2020, 'Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation', Cell Metabolism, vol. 31, no. 5, pp. 909-919.e8. https://doi.org/10.1016/j.cmet.2020.03.017

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title = "Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation",

abstract = "Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.",

keywords = "glycemia, insulin resistance, ketone bodies, ketone body oxidation, obesity, pimozide, type 2 diabetes",

author = "{Al Batran}, Rami and Keshav Gopal and Capozzi, {Megan E.} and Chahade, {Jadin J.} and Bruno Saleme and Tabatabaei-Dakhili, {S. Amirhossein} and Greenwell, {Amanda A.} and Jingjing Niu and Malak Almutairi and Byrne, {Nikole J.} and Grant Masson and Ryekjang Kim and Farah Eaton and Mulvihill, {Erin E.} and L{\'e}a Garneau and Masters, {Andrea R.} and Zeruesenay Desta and Vel{\'a}zquez-Mart{\'i}nez, {Carlos A.} and C{\'e}line Aguer and Crawford, {Peter A.} and Gopinath Sutendra and Campbell, {Jonathan E.} and Dyck, {Jason R.B.} and Ussher, {John R.}",

note = "Funding Information: The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709. We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant (5U2C-DK093000). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C. an Allocation Jeune Chercheur from the Soci{\'e}t{\'e} Francophone du Diab{\'e}te to C.A. and a Project Grant and Foundation Grant to G.S. and J.R.B.D. respectively, from the CIHR. Conceptualization, R.A. and J.R.U.; Investigation, R.A. K.G. M.E.C. J.J.C. B.S. S.A.T.D. A.A.G. J.N. M.A. N.J.B. G.M. R.K. F.E. E.E.M. L.G. A.R.M. and C.A.; Formal Analysis and Visualization, R.A. and K.G.; Writing – Original Draft, R.A. and J.R.U.; Writing – Review & Editing, R.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Funding Acquisition and Project Administration, J.R.U.; Resources, Z.D. C.V. C.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Supervision, J.R.U. J.R.U. takes full responsibility for the data within this paper. The University of Alberta has filed a patent application regarding the subject matter of this article. Funding Information: The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709 . We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant ( 5U2C-DK093000 ). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C., an Allocation Jeune Chercheur from the Soci{\'e}t{\'e} Francophone du Diab{\'e}te to C.A., and a Project Grant and Foundation Grant to G.S. and J.R.B.D., respectively, from the CIHR. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = may,

day = "5",

doi = "10.1016/j.cmet.2020.03.017",

language = "English (US)",

volume = "31",

pages = "909--919.e8",

journal = "Cell Metabolism",

issn = "1550-4131",

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T1 - Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation

AU - Al Batran, Rami

AU - Gopal, Keshav

AU - Capozzi, Megan E.

AU - Chahade, Jadin J.

AU - Saleme, Bruno

AU - Tabatabaei-Dakhili, S. Amirhossein

AU - Greenwell, Amanda A.

AU - Niu, Jingjing

AU - Almutairi, Malak

AU - Byrne, Nikole J.

AU - Masson, Grant

AU - Kim, Ryekjang

AU - Eaton, Farah

AU - Mulvihill, Erin E.

AU - Garneau, Léa

AU - Masters, Andrea R.

AU - Desta, Zeruesenay

AU - Velázquez-Martínez, Carlos A.

AU - Aguer, Céline

AU - Crawford, Peter A.

AU - Sutendra, Gopinath

AU - Campbell, Jonathan E.

AU - Dyck, Jason R.B.

AU - Ussher, John R.

N1 - Funding Information: The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709. We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant (5U2C-DK093000). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C. an Allocation Jeune Chercheur from the Société Francophone du Diabéte to C.A. and a Project Grant and Foundation Grant to G.S. and J.R.B.D. respectively, from the CIHR. Conceptualization, R.A. and J.R.U.; Investigation, R.A. K.G. M.E.C. J.J.C. B.S. S.A.T.D. A.A.G. J.N. M.A. N.J.B. G.M. R.K. F.E. E.E.M. L.G. A.R.M. and C.A.; Formal Analysis and Visualization, R.A. and K.G.; Writing – Original Draft, R.A. and J.R.U.; Writing – Review & Editing, R.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Funding Acquisition and Project Administration, J.R.U.; Resources, Z.D. C.V. C.A. P.A.C. G.S. J.E.C. J.R.B.D. and J.R.U.; Supervision, J.R.U. J.R.U. takes full responsibility for the data within this paper. The University of Alberta has filed a patent application regarding the subject matter of this article. Funding Information: The HTS molecular modeling studies required access to the Compute Canada and Westgrid online servers. The authors would like to especially thank the dedicated staff working at The Metabolomics Innovation Centre (TMIC), where the metabolomic profiling was carried out. In addition, mass spectrometry work and non-compartmental analysis was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine, a facility supported by the IU Simon Cancer Center Support Grant P30 CA082709 . We would also like to thank Christine Bach for her work on method development. Part of this study was conducted at the National Mouse Metabolic Phenotyping Center at UMass Medical School funded by a National Institutes of Health (NIH) grant ( 5U2C-DK093000 ). R.A. is a postdoctoral fellow of the Canadian Institutes of Health Research (CIHR) and Diabetes Canada. G.S. is a National New Investigator of the Heart and Stroke Foundation of Canada, J.E.C. is a Borden Scholar, and J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity). This work was supported by a Career Development Award from the American Diabetes Association (1-18-JDF-017) and an NIH grant (DK123075) to J.E.C., an Allocation Jeune Chercheur from the Société Francophone du Diabéte to C.A., and a Project Grant and Foundation Grant to G.S. and J.R.B.D., respectively, from the CIHR. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/5/5

Y1 - 2020/5/5

N2 - Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

AB - Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-induced type 2 diabetes (T2D), though whether alterations in ketone body metabolism influence T2D pathology is unknown. We report here that activity of the rate-limiting enzyme for ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidine pimozide, which is approved to suppress tics in individuals with Tourette syndrome, is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia in mice, which was phenocopied in mice with muscle-specific Oxct1/SCOT deficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limiting enzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obese mice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone body oxidation to the pathology of obesity-induced T2D, while suggesting pharmacological SCOT inhibition as a new class of anti-diabetes therapy.

KW - glycemia

KW - insulin resistance

KW - ketone bodies

KW - ketone body oxidation

KW - obesity

KW - pimozide

KW - type 2 diabetes

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Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation

Abstract

Bibliographical note

Keywords

UN SDGs

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