Tong Qingchun, Ye ChianPing, McCrimmon Rory J, Dhillon Harveen, Choi Brian, Kramer Melissa D, Yu Jia, Yang Zongfang, Christiansen Lauryn M, Lee Charlotte E, Choi Cheol Soo, Zigman Jeffrey M, Shulman Gerald I, Sherwin Robert S, Elmquist Joel K, Lowell Bradford B
Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, MA 02215, USA.
Cell Metab. 2007 May;5(5):383-93. doi: 10.1016/j.cmet.2007.04.001.
The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia.
神经肽在下丘脑中的重要性已通过实验得到证实。由于在体内评估功能存在困难，快速作用的神经递质谷氨酸和γ-氨基丁酸（GABA）的作用在很大程度上尚不清楚。囊泡转运体（谷氨酸的VGLUTs和GABA的VGAT）是囊泡摄取以及神经递质突触释放所必需的。腹内侧下丘脑（VMH）神经元主要是谷氨酸能的，并表达VGLUT2。为了评估VMH神经元释放谷氨酸的作用，我们构建了在SF1神经元（VMH神经元的一个主要亚群）中选择性缺失VGLUT2的小鼠。这些小鼠在禁食期间出现低血糖，这是由于禁食诱导的升糖胰腺激素胰高血糖素增加受损，以及肝脏中编码PGC-1α和糖异生酶磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖-6-磷酸酶（G6Pase）的mRNA诱导受损所致。同样，这些小鼠对胰岛素诱导的低血糖和2-脱氧葡萄糖（一种抗代谢物）的对抗调节反应存在缺陷。因此，VMH神经元释放谷氨酸是预防低血糖的神经回路的一个重要组成部分。
