HMG-CoA synthase 2 drives brain metabolic reprogramming in cocaine exposure
HMG-CoA synthase 2 drives brain metabolic reprogramming in cocaine exposure
复制标题
HMG-CoA 合酶 2 在可卡因暴露中驱动大脑代谢重编程
DOI：
10.1016/j.neuropharm.2017.10.001
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发表时间：
2019-04-01
影响因子：
4.7
通讯作者：
Cen，Xiaobo
中科院分区：
文献类型：
--
作者：
Shao，Xue;Tang，Yunxuan;Cen，Xiaobo
大脑是一个高能量消耗的器官，通常利用葡萄糖作为大脑活动的主要能量来源。当葡萄糖在应激条件下变得稀缺时，酮体变得极其重要，如β-羟基丁酸酯、乙酰乙酸酯和丙酮。在精神刺激性药物滥用者中已经观察到大脑能量代谢的变化；然而，可卡因依赖中大脑代谢编程的模式在很大程度上仍然不清楚。在这里，我们描述了暴露于可卡因的小鼠脑伏隔核(NAC)的代谢物和代谢酶。我们发现，可卡因改变了NAC的能量代谢，并显著激活了NAC的酮生成途径。关键的酮合成限速酶HMG-CoA合成酶2(HMGCS2)的表达明显上调。在通过葡萄糖激酶的激活将代谢途径从酮生成转换到糖酵解后，可卡因引起的代谢重编程恢复了稳态，可卡因的作用减弱。重要的是，HMGCS2的药理和遗传抑制都显著抑制了可卡因诱导酮的发生和行为。综上所述，可卡因在NAC中诱导了显著的能量重编程，其特征是HMGCS2驱动的酮类生成。这种效应可能会促进大脑对可卡因诱导的能量压力的适应。我们的发现建立了药物诱导的能量重编程和可卡因效应之间的重要联系，并可能对可卡因成瘾的治疗有指导意义。
The brain is a high energy-consuming organ that typically utilizes glucose as the main energy source for cerebral activity. When glucose becomes scarce under conditions of stress, ketone bodies, such as β-hydroxybutyrate, acetoacetate and acetone, become extremely important. Alterations in brain energy metabolism have been observed in psychostimulant abusers; however, the mode of brain metabolic programming in cocaine dependence remains largely unknown. Here, we profiled the metabolites and metabolic enzymes from brain nucleus accumbens (NAc) of mice exposed to cocaine. We found that cocaine modified energy metabolism and markedly activated ketogenesis pathway in the NAc. The expression of HMG-CoA synthase 2 (HMGCS2), a critical rate-limiting ketogenesis enzyme, was markedly up-regulated. After switching metabolic pathways from ketogenesis to glycolysis through activation of glucokinase, cocaine-evoked metabolic reprogramming regained homeostasis, and the cocaine effect was attenuated. Importantly, both the pharmacological and genetic inhibition of HMGCS2 significantly suppressed cocaine-induced ketogenesis and behavior. In conclusion, cocaine induces a remarkable energy reprogramming in the NAc, which is characterized by HMGCS2-driven ketogenesis. Such effect may facilitate adaptations to cocaine-induced energy stress in the brain. Our findings establish an important link between drug-induced energy reprogramming and cocaine effect, and may have implication in the treatment of cocaine addiction.