匹莫齐特或可减轻肥胖引起的高血糖症 作者: 发布时间:/4/14 13:49:56 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4月9日在线发表于《细胞 代谢》。
研究人员发现,酮体氧化速率限制酶(琥珀酰-CoA:3-酮酸-CoA转移酶,SCOT/Oxct1)的活性在肥胖小鼠肌肉中升高。他们还发现,被批准用于抑制Tourette综合征患者抽搐的匹莫齐特是SCOT的拮抗剂。匹莫齐特治疗可逆转肥胖引起的小鼠高血糖症,这种现象在具有肌肉特异性Oxct1/SCOT缺乏的小鼠中可实现表型重复。 这些作用取决于丙酮酸脱氢酶(PDH/Pdha1)活性、葡萄糖氧化的限速酶,因为匹莫齐特不能缓解肌肉特异性Pdha1/PDH缺乏肥胖小鼠的高血糖症。这项工作定义了增强的酮体氧化对肥胖诱导的2型糖尿病(T2D)发病的基本贡献,同时认为对SCOT的药理抑制可作为一种新的糖尿病疗法。 据悉,尽管酮体代谢的改变是否影响T2D病理尚不清楚,但是碳水化合物、脂质和蛋白质代谢的扰动会导致肥胖引起的2型糖尿病(T2D)。 附:英文原文 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, L a Garneau, Andrea R. Masters, Zeruesenay Desta, Carlos A. Vel zquez-Mart nez, C line Aguer, Peter A. Crawford, Gopinath Sutendra, Jonathan E. Campbell, Jason R.B. Dyck, John R. Ussher
Issue Volume: -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..03.017
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期刊信息
Cell Metabolism:《细胞 代谢》,创刊于。隶属于细胞出版社,最新IF:22.415
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