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

Animals Diet / adverse effects Hyperglycemia / chemically induced Hypoglycemic Agents / pharmacology Ketones / antagonists & inhibitors Male Mice Muscle, Skeletal / drug effects Obesity / chemically induced Oxidation-Reduction Pimozide / pharmacology Streptozocin
glycemia insulin resistance ketone bodies ketone body oxidation obesity pimozide type 2 diabetes

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
05 05 2020
Historique:
received: 29 10 2019
revised: 31 01 2020
accepted: 24 03 2020
pubmed: 11 4 2020
medline: 10 11 2021
entrez: 11 4 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cmet.2020.03.017 PMID: 32275862
pubmed: 32275862
pii: S1550-4131(20)30132-7
doi: 10.1016/j.cmet.2020.03.017
pii:
doi:

Substances chimiques

Hypoglycemic Agents 0
Ketones 0
Pimozide 1HIZ4DL86F
Streptozocin 5W494URQ81

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

909-919.e8

Subventions

Organisme : NIDDK NIH HHS
ID : F32 DK116542
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK123075
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA082709
Pays : United States
Organisme : NIDDK NIH HHS
ID : U2C DK093000
Pays : United States
Organisme : CIHR
Pays : Canada

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The University of Alberta has filed a patent application regarding the subject matter of this article.

Auteurs

Rami 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.

Keshav 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.

Megan E Capozzi (ME)

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.

Jadin J 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.

Bruno Saleme (B)

Department of Medicine, University of Alberta, Edmonton, AB, Canada.

S Amirhossein Tabatabaei-Dakhili (SA)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

Amanda A 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.

Jingjing Niu (J)

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.

Malak 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.

Nikole J 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.

Grant 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.

Ryekjang 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.

Farah 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.

Erin E Mulvihill (EE)

Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; University of Ottawa Heart Institute, Ottawa, ON, Canada.

Léa Garneau (L)

Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada; Institut du Savoir Montfort, Ottawa, ON, Canada.

Andrea R Masters (AR)

Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Zeruesenay Desta (Z)

Department of Medicine, Division of Clinical Pharmacology, Indianapolis, IN, USA.

Carlos A Velázquez-Martínez (CA)

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.

Céline 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.

Peter A Crawford (PA)

Division of Molecular Medicine, Department of Medicine, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN, USA.

Gopinath Sutendra (G)

Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Jonathan E Campbell (JE)

Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.

Jason R B 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.

John R 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.

Articles similaires

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Meal Timing and Anthropometric and Metabolic Outcomes: A Systematic Review and Meta-Analysis.

Hiu Yee Liu, Ashley A Eso, Nathan Cook et al.
1.00
Humans Meals Time Factors Female Adult

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Phénomènes physiologiques › Alimentation et nutrition › Phénomènes physiologiques nutritionnels › Régime alimentaire › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles du métabolisme du glucose › Hyperglycémie › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Hypoglycémiants › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Composés chimiques organiques › Cétones › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Tissus › Muscles › Muscle strié › Muscles squelettiques › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Obésité › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Métabolisme › Métabolisme énergétique › Oxydoréduction › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Benzimidazoles › Pimozide › Pimozide Alleviates Hyperglycemia in...
questionsmedicales.fr › Glucides › Hétérosides › Aminosides › Streptozocine › Pimozide Alleviates Hyperglycemia in...