Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada; Cardiovascular Research Centre, University of Alberta, Edmonton, AB, Canada.
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
Cell Metab. 2020 May 5;31(5):909-919.e8. doi: 10.1016/j.cmet.2020.03.017. Epub 2020 Apr 9.
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.
碳水化合物、脂质和蛋白质代谢的紊乱会导致肥胖引起的 2 型糖尿病（T2D），尽管酮体代谢的改变是否会影响 T2D 病理还不清楚。我们在这里报告，酮体氧化的限速酶琥珀酰辅酶 A：3-酮酸辅酶 A 转移酶（SCOT/Oxct1）的活性在肥胖小鼠的肌肉中增加。我们还发现，批准用于抑制妥瑞氏症患者抽搐的二苯丁基哌啶匹莫齐是一种 SCOT 拮抗剂。匹莫齐治疗可逆转肥胖小鼠的高血糖，在肌肉特异性 Oxct1/SCOT 缺陷小鼠中出现类似表型。这些作用依赖于丙酮酸脱氢酶（PDH/Pdha1）活性，即葡萄糖氧化的限速酶，因为匹莫齐未能缓解肌肉特异性 Pdha1/PDH 缺陷肥胖小鼠的高血糖。这项工作定义了增强的酮体氧化对肥胖引起的 T2D 病理的基本贡献，同时表明 SCOT 抑制的药理学作用可能是一种新的抗糖尿病疗法。
