Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, USA.
Neuropeptides. 2013 Jun;47(3):139-47. doi: 10.1016/j.npep.2013.01.004. Epub 2013 Mar 13.
The hypothalamic neurochemicals neuropeptide Y (NPY), orexin-A (ORX), and oxytocin (OXY) exert glucoregulatory effects upon intracerebral administration, findings that support their potential function within neural pathways that maintain glucostasis. Current understanding of how these neurotransmitter systems respond to the diabetes mellitus complication, insulin-induced hypoglycemia, is limited to knowledge of neuropeptide gene transcriptional reactivity. We investigated the hypothesis that hypoglycemia elicits hypothalamic site-specific alterations in levels of these neurochemicals, and that adjustments in local neurotransmitter availability may be regulated by catecholaminergic (CA) input from the caudal dorsomedial hindbrain. The arcuate (ARH) and paraventricular (PVH) hypothalamic nuclei and lateral hypothalamic area (LHA) were each microdissected from adult male rats pretreated by caudal fourth ventricular administration of the selective CA neurotoxin, 6-hydroxydopamine (6-OHDA), or vehicle prior to insulin (INS)-induced hypoglycemia. Hypoglycemia stimulated ARH NPY gene expression and NPY accumulation in the ARH and LHA, but not PVH. 6-OHDA pretreatment did not modify the positive NPY mRNA response to INS, but blunted hypoglycemic augmentation of ARH and LHA NPY content while increasing PVH NPY levels in response to hypoglycemia. INS-treated rats exhibited diminished LHA ORX gene expression and increased [ARH; LHA] or decreased [PVH] tissue ORX protein levels. 6-OHDA+INS animals showed a comparable decline in ORX transcripts, but attenuated augmentation of ARH and LHA ORX content and elevated PVH ORX levels. OT mRNA and protein were respectively decreased or unchanged during hypoglycemia, responses that were uninfluenced by hindbrain CA nerve cell destruction. These results illustrate divergent adjustments in glucoregulatory neurotransmitter gene expression and site-specific protein accumulation in the hypothalamus during hypoglycemia. Evidence that 6-OHDA pretreatment does not modify NPY or ORX transcriptional reactivity to hypoglycemia, but alters hypoglycemic patterns of NPY and ORX accretion implicates dorsomedial hindbrain CA neurons in regulation of translation/post-translational processing and site-specific availability of these neurotransmitters in the hypothalamus during hypoglycemia.
下丘脑神经化学物质神经肽 Y（NPY）、食欲素-A（ORX）和催产素（OXY）在脑内给药时发挥血糖调节作用，这一发现支持了它们在维持血糖稳定的神经通路中的潜在功能。目前对于这些神经递质系统如何应对糖尿病并发症——胰岛素诱导的低血糖的了解仅限于神经肽基因转录反应的知识。我们研究了这样一个假设，即低血糖会引起下丘脑特定部位这些神经化学物质水平的改变，而局部神经递质的可用性可能受到来自尾侧背内侧后脑的儿茶酚胺（CA）输入的调节。弓状核（ARH）和室旁核（PVH）下丘脑核以及外侧下丘脑区（LHA）分别从小鼠中分离出来，这些小鼠在接受胰岛素（INS）诱导的低血糖之前，通过第四脑室尾侧给予选择性 CA 神经毒素 6-羟多巴胺（6-OHDA）或载体进行预处理。低血糖刺激 ARH 的 NPY 基因表达和 ARH 和 LHA 中的 NPY 积累，但不刺激 PVH 的 NPY 基因表达。6-OHDA 预处理不会改变 INS 诱导的 NPY mRNA 的正反应，但会减弱低血糖对 ARH 和 LHA NPY 含量的增强作用，同时增加低血糖时 PVH NPY 水平。INS 处理的大鼠表现出 LHA ORX 基因表达减少和 [ARH；LHA]或 [PVH]组织 ORX 蛋白水平降低。6-OHDA+INS 动物的 ORX 转录物下降幅度相似，但 ARH 和 LHA ORX 含量的增强和 PVH ORX 水平的升高减弱。低血糖期间 OT mRNA 和蛋白分别减少或不变，这些反应不受后脑 CA 神经细胞破坏的影响。这些结果表明，在低血糖期间，下丘脑的葡萄糖调节神经递质基因表达和特定部位的蛋白质积累存在不同的调节。证据表明，6-OHDA 预处理不会改变 NPY 或 ORX 对低血糖的转录反应性，但改变了低血糖时 NPY 和 ORX 积累的模式，这表明背侧后脑 CA 神经元参与调节这些神经递质在低血糖时的翻译/翻译后加工和特定部位的可用性。
