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Publication
Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal
Muscle Ketone Oxidation.
Authors 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
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Cell Metabolism
Year 2020
Date Published 5/1/2020
Volume : Pages 31 : 909 - 919.e8
PubMed Reference 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-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.




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