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Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation.
Al Batran, Rami; Gopal, Keshav; Capozzi, Megan E; Chahade, Jadin J; Saleme, Bruno; Tabatabaei-Dakhili, S Amirhossein; Greenwell, Amanda A; Niu, Jingjing; Almutairi, Malak; Byrne, Nikole J; Masson, Grant; Kim, Ryekjang; Eaton, Farah; Mulvihill, Erin E; Garneau, Léa; Masters, Andrea R; Desta, Zeruesenay; Velázquez-Martínez, Carlos A; Aguer, Céline; Crawford, Peter A; Sutendra, Gopinath; Campbell, Jonathan E; Dyck, Jason R B; Ussher, John R.
Affiliation
  • Al Batran R; 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.
  • Gopal K; 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.
  • Capozzi ME; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  • Chahade JJ; 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.
  • Saleme B; Department of Medicine, University of Alberta, Edmonton, AB, Canada.
  • Tabatabaei-Dakhili SA; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • Greenwell AA; 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.
  • Niu J; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  • Almutairi M; 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.
  • Byrne NJ; 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.
  • Masson G; 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.
  • Kim R; 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.
  • Eaton F; 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.
  • Mulvihill EE; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.
  • Garneau L; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; Institut du Savoir Montfort, Ottawa, ON, Canada.
  • Masters AR; Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
  • Desta Z; Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN, USA.
  • Velázquez-Martínez CA; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
  • Aguer C; 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.
  • Crawford PA; Division of Molecular Medicine, Department of Medicine, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.
  • Sutendra G; Department of Medicine, University of Alberta, Edmonton, AB, Canada.
  • Campbell JE; Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
  • Dyck JRB; 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.
  • Ussher JR; 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.
Cell Metab ; 31(5): 909-919.e8, 2020 05 05.
Article in En | MEDLINE | ID: mdl-32275862
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-CoA3-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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pimozide / Muscle, Skeletal / Hyperglycemia / Hypoglycemic Agents / Ketones / Obesity Limits: Animals Language: En Journal: Cell Metab Journal subject: METABOLISMO Year: 2020 Document type: Article Affiliation country: Canadá
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pimozide / Muscle, Skeletal / Hyperglycemia / Hypoglycemic Agents / Ketones / Obesity Limits: Animals Language: En Journal: Cell Metab Journal subject: METABOLISMO Year: 2020 Document type: Article Affiliation country: Canadá