Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone
Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone
复制标题
DOI：
10.1172/jci200421620
复制
发表时间：
2004-08-01
影响因子：
15.9
通讯作者：
Nillni, EA
中科院分区：
文献类型：
--
作者：
Sanchez, VC;Goldstein, J;Nillni, EA
瘦素调节能量平衡涉及几种神经肽的调节，包括促甲状腺素释放激素（TRH）。由一个较大的无活性前体合成，其成熟需要激素原转化酶1和2 （PC1和PC2）的蛋白水解裂解。由于这种对瘦素的成熟反应需要激素原加工，我们假设瘦素可能调节下丘脑PC1和PC2的表达，最终导致激素原协调加工成成熟肽。利用下丘脑神经元，我们发现瘦素刺激了转染的293T细胞中PC1和PC2 mRNA和蛋白的表达，并增加了PC1和PC2启动子的活性。饥饿大鼠导致血清瘦素水平降低，下丘脑室旁核（PVN）中pci和PC2基因及蛋白表达降低。给禁食动物外源性瘦素使中隆起（ME）和PVN的PC1水平恢复到与喂养的对照动物相近的水平。与PVN中pc的这种调节一致，禁食动物PVN和ME中TRH浓度相对于喂养动物大幅降低，瘦素逆转了这种下降。进一步的分析表明，促甲状腺素释放激素（prothyro促甲状腺素释放激素，prothyroin -releasing hormone，简称progh）在已知PC裂解位点的蛋白水解裂解在禁食的动物中减少，而在给予瘦素的动物中增加。综上所述，这些研究结果表明，瘦素依赖性刺激下丘脑TRH表达既包括TRH转录的激活，也包括PC1和PC2表达的刺激，从而促进了progh向成熟TRH的加工。
Regulation of energy balance by leptin involves regulation of several neuropeptides, including thyrotropin-releasing hormone (TRH). Synthesized from a larger inactive precursor, its maturation requires proteolytic cleavage by prohormone convertases 1 and 2 (PC1 and PC2). Since this maturation in response to leptin requires prohormone processing, we hypothesized that leptin might regulate hypothalamic PC1 and PC2 expression, ultimately leading to coordinated processing of prohormones into mature peptides. Using hypothalamic neurons, we found that leptin stimulated PC1 and PC2 mRNA and protein expression and also increased PC1 and PC2 promoter activities in transfected 293T cells. Starvation of rats, leading to low serum leptin levels, decreased PC I and PC2 gene and protein expression in the paraventricular nucleus (PVN) of the hypothalamus. Exogenous administration of leptin to fasted animals restored PC1 levels in the median eminence (ME) and the PVN to approximately the level found in fed control animals. Consistent with this regulation of PCs in the PVN, concentrations of TRH in the PVN and ME were substantially reduced in the fasted animals relative to the fed animals, and leptin reversed this decrease. Further analysis showed that proteolytic cleavage of pro-thyrotropin-releasing hormone (proTRH) at known PC cleavage sites was reduced by fasting and increased in animals given leptin. Combined, these findings suggest that leptin-dependent stimulation of hypothalamic TRH expression involves both activation of trh transcription and stimulation of PC1 and PC2 expression, which lead to enhanced processing of proTRH into mature TRH.