Sanchez Vanesa C, Goldstein Jorge, Stuart Ronald C, Hovanesian Virginia, Huo Lihong, Munzberg Heike, Friedman Theodore C, Bjorbaek Christian, Nillni Eduardo A
Division of Endocrinology, Department of Medicine, Brown Medical School, Rhode Island Hospital, Providence, Rhode Island 02903, USA.
J Clin Invest. 2004 Aug;114(3):357-69. doi: 10.1172/JCI21620.
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 PC1 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.
瘦素对能量平衡的调节涉及对多种神经肽的调节，包括促甲状腺激素释放激素（TRH）。TRH由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）进行蛋白水解切割。由于这种对瘦素的反应性成熟需要激素原加工，我们推测瘦素可能调节下丘脑PC1和PC2的表达，最终导致激素原协同加工成成熟肽。利用下丘脑神经元，我们发现瘦素刺激PC1和PC2的mRNA和蛋白表达，并且还增加了转染的293T细胞中PC1和PC2启动子的活性。大鼠饥饿导致血清瘦素水平降低，下丘脑室旁核（PVN）中PC1和PC2的基因及蛋白表达减少。给禁食动物外源性注射瘦素可使正中隆起（ME）和PVN中的PC1水平恢复至与进食对照动物中大致相同的水平。与PVN中PCs的这种调节一致，相对于进食动物，禁食动物PVN和ME中TRH的浓度大幅降低，而瘦素可逆转这种降低。进一步分析表明，禁食会减少已知PC切割位点处促甲状腺激素释放激素原（proTRH）的蛋白水解切割，而给动物注射瘦素则会增加这种切割。综合这些发现表明，瘦素依赖性刺激下丘脑TRH表达涉及trh转录的激活以及PC1和PC2表达的刺激，这导致proTRH加工成成熟TRH的过程增强。
