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Tabatabaei Dakhili SA et al - All Supplementary Materials - Nov 04 2022.pdf (1.47 MB)

The antipsychotic dopamine 2 receptor antagonist diphenylbutylpiperidines improve glycemia in experimental obesity by inhibiting succinyl-CoA:3-ketoacid CoA transferase

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Version 2 2022-11-08, 14:53
Version 1 2022-10-18, 19:19
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posted on 2022-11-08, 14:53 authored by Seyed Amirhossein Tabatabaei Dakhili, Amanda A. Greenwell, Kunyan Yang, Rabih Abou Farraj, Christina T. Saed, Keshav Gopal, Jordan S. F. Chan, Jadin J. Chahade, Farah Eaton, Crystal Lee, Carlos A. Velazquez-Martinez, Peter A. Crawford, J. N. Mark Glover, Rami Al Batran, John R. Ussher

Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), it remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent, pimozide, is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We have now extended those observations herein, using computer-assisted in silico modelling and in vivo pharmacology studies that highlight SCOT as a noncanonical target shared amongst the diphenylbutylpiperidine (DPBP) drug class, which includes penfluridol and fluspirilene. All 3 DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demonstrated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, suggesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D. 

Funding

This work was supported by Project Grants to J.R.U. from the Canadian Institutes of Health Research. J.R.U. is a Tier 2 Canada Research Chair (Pharmacotherapy of Energy Metabolism in Obesity).

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