Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, La 71201, USA.
Neuroendocrinology. 2010;91(1):56-63. doi: 10.1159/000264919. Epub 2009 Dec 7.
It has been reported that adrenalectomy (ADX) and the potent type II glucocorticoid receptor agonist, dexamethasone, exert opposing effects on glucose utilization in specific brain regions, including the hypothalamus. The present study investigated the hypothesis that ADX alters neuronal substrate fuel transporter mRNA levels in characterized hypothalamic and hindbrain metabolic monitoring structures, and adjustments in these gene profiles are correlated with modified transcription of genes encoding the glucose sensor, glucokinase (GCK), and the energy-dependent, inwardly-rectifying potassium channel, K(ATP). The lateral hypothalamic area (LHA), ventromedial hypothalamic nucleus (VMN), and dorsal vagal complex (DVC) were microdissected from ADX and sham-operated male rats 2 h after neutral protamine Hagedorn insulin or vehicle injection, and evaluated by quantitative real-time RT-PCR for neuronal glucose (GLUT3, GLUT4), monocarboxylate (MCT2) transporter, GCK, and sulfonylurea receptor-1 (SUR1) mRNA content. ADX modified basal fuel transporter and energy transducer gene expression in a site-specific manner since this manipulation decreased MCT2 and GLUT3 transcription in the DVC only; increased or decreased GCK mRNA in the LHA and VMN, respectively; and decreased SUR1 gene profiles in the DVC and LHA. Adrenal removal did not alter baseline GLUT4 mRNA in any structure examined. ADX also prevented the following transcriptional responses to insulin-induced hypoglycemia: downregulated DVC MCT2, downregulated DVC and upregulated LHA and VMN GLUT3, upregulated LHA GLUT4, upregulated LHA GCK, and upregulated VMN SUR1. These results show that the adrenals regulate basal GLUT3 gene profiles in the DVC alone; during hypoglycemia, these glands suppress (DVC) or increase GLUT3 (LHA and VMH) mRNA, and selectively elevate GLUT4 transcripts in the LHA. The data demonstrate divergent adrenal control of DVC neuronal monocarboxylate transporter gene expression under basal (stimulatory) versus hypoglycemic (inhibitory) conditions. The current work also reveals contrasting adrenal regulation of baseline GCK mRNA in the LHA (inhibitory) and VMN (stimulatory), as well as adrenal-dependent hypoglycemic enhancement of LHA GCK and VMN SUR1 gene profiles. Additional research is required to characterize the impact of adrenal-sensitive substrate transporter and metabolic transducer function on fuel uptake and metabolic regulatory signaling in these brain sites.
据报道，肾上腺切除术（ADX）和强效 II 型糖皮质激素受体激动剂地塞米松对下丘脑等特定脑区的葡萄糖利用有相反的影响。本研究假设 ADX 会改变下丘脑和后脑代谢监测结构中神经元底物燃料转运体 mRNA 水平，并且这些基因谱的调整与葡萄糖传感器葡激酶（GCK）和能量依赖性内向整流钾通道（KATP）的基因转录的改变相关。在中性蛋白精氨酸 Hagedorn 胰岛素或载体注射后 2 小时，从 ADX 和假手术雄性大鼠中分离出外侧下丘脑区域（LHA）、腹内侧下丘脑核（VMN）和背侧迷走复合体（DVC），并通过定量实时 RT-PCR 评估神经元葡萄糖（GLUT3、GLUT4）、单羧酸（MCT2）转运体、GCK 和磺酰脲受体-1（SUR1）mRNA 含量。ADX 以特定于部位的方式改变了基础燃料转运体和能量转导基因的表达，因为这种操作仅降低了 DVC 中的 MCT2 和 GLUT3 转录；分别增加或减少 LHA 和 VMN 中的 GCK mRNA；并降低 DVC 和 LHA 中的 SUR1 基因谱。肾上腺切除未改变任何检查结构中的基础 GLUT4 mRNA。ADX 还阻止了胰岛素诱导的低血糖反应的以下转录反应：下调 DVC MCT2，下调 DVC 和上调 LHA 和 VMN GLUT3，上调 LHA GLUT4，上调 LHA GCK，上调 VMN SUR1。这些结果表明，肾上腺单独调节 DVC 中的基础 GLUT3 基因谱；在低血糖期间，这些腺体抑制（DVC）或增加 GLUT3（LHA 和 VMH）mRNA，并选择性地增加 LHA 中的 GLUT4 转录物。该数据表明，在基础（刺激）和低血糖（抑制）条件下，肾上腺对 DVC 神经元单羧酸转运体基因表达的控制不同。目前的工作还揭示了 LHA（抑制性）和 VMN（刺激性）中基础 GCK mRNA 的肾上腺不同调节，以及肾上腺依赖的低血糖增强 LHA GCK 和 VMN SUR1 基因谱。需要进一步研究以表征肾上腺敏感底物转运体和代谢转导器功能对这些脑区中燃料摄取和代谢调节信号的影响。
