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

Research output: Contribution to journalArticle

2 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 languageEnglish (US)
Pages (from-to)909-919.e8
JournalCell Metabolism
Volume31
Issue number5
DOIs
StatePublished - May 5 2020
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    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