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

Cell Metab. 2020 May 5;31(5):909-919.e8. doi: 10.1016/j.cmet.2020.03.017. Epub 2020 Apr 9.

Authors

Rami Al Batran¹, Keshav Gopal¹, Megan E Capozzi², Jadin J Chahade¹, Bruno Saleme³, S Amirhossein Tabatabaei-Dakhili⁴, Amanda A Greenwell¹, Jingjing Niu², Malak Almutairi¹, Nikole J Byrne⁵, Grant Masson⁵, Ryekjang Kim¹, Farah Eaton¹, Erin E Mulvihill⁶, Léa Garneau⁷, Andrea R Masters⁸, Zeruesenay Desta⁹, Carlos A Velázquez-Martínez⁴, Céline Aguer¹⁰, Peter A Crawford¹¹, Gopinath Sutendra³, Jonathan E Campbell², Jason R B Dyck⁵, John R Ussher¹²

Affiliations

¹ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.
² Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
³ Department of Medicine, University of Alberta, Edmonton, AB, Canada.
⁴ Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
⁵ Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada; Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
⁶ Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
⁷ Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; Institut du Savoir Montfort, Ottawa, ON, Canada.
⁸ Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
⁹ Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN, USA.
¹⁰ Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; Institut du Savoir Montfort, Ottawa, ON, Canada; School of Human Kinetics, University of Ottawa, Ottawa, ON, Canada.
¹¹ Division of Molecular Medicine, Department of Medicine, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
¹² Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada. Electronic address: jussher@ualberta.ca.

PMID: 32275862
DOI: 10.1016/j.cmet.2020.03.017

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diet / adverse effects
Hyperglycemia / chemically induced
Hyperglycemia / drug therapy*
Hypoglycemic Agents / pharmacology*
Ketones / antagonists & inhibitors*
Ketones / metabolism
Male
Mice
Muscle, Skeletal / drug effects*
Muscle, Skeletal / metabolism
Obesity / chemically induced
Obesity / drug therapy*
Oxidation-Reduction
Pimozide / pharmacology*
Streptozocin

Substances

Hypoglycemic Agents
Ketones
Pimozide
Streptozocin

Abstract

Publication types

MeSH terms

Substances

Grants and funding