加拿大阿尔伯塔大学John R. Ussher研究小组发现，匹莫齐特通过抑制骨骼肌酮氧化来减轻饮食引起的肥胖症中的高血糖症。该研究于2020年4月9日在线发表于《细胞—代谢》。

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

Author: 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. Crawford, Gopinath Sutendra, Jonathan E. Campbell, Jason R.B. Dyck, John R. Ussher

Issue&Volume: 2020-04-09

Abstract: Perturbations in carbohydrate, lipid, and protein metabolism contribute to obesity-inducedtype 2 diabetes (T2D), though whether alterations in ketone body metabolism influenceT2D pathology is unknown. We report here that activity of the rate-limiting enzymefor ketone body oxidation, succinyl-CoA:3-ketoacid-CoA transferase (SCOT/Oxct1), is increased in muscles of obese mice. We also found that the diphenylbutylpiperidinepimozide, which is approved to suppress tics in individuals with Tourette syndrome,is a SCOT antagonist. Pimozide treatment reversed obesity-induced hyperglycemia inmice, which was phenocopied in mice with muscle-specific Oxct1/SCOTdeficiency. These actions were dependent on pyruvate dehydrogenase (PDH/Pdha1) activity, the rate-limitingenzyme of glucose oxidation, as pimozide failed to alleviate hyperglycemia in obesemice with a muscle-specific Pdha1/PDH deficiency. This work defines a fundamental contribution of enhanced ketone bodyoxidation to the pathology of obesity-induced T2D, while suggesting pharmacologicalSCOT inhibition as a new class of anti-diabetes therapy.

DOI: 10.1016/j.cmet.2020.03.017

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30132-7