Kiss1/Gpr54触发下丘脑GnRH节律性分泌是性发育启动研究的重大发现，但Kiss1/Gpr54基因表达及转录异常并不能解释大部分性发育启动异常。除调节性发育外，Kiss14/Gpr5还与糖代谢及体重控制相关。前期及预实验发现：除转录因子外，Kiss1表达还受营养影响；性早熟女童代谢产物、肠道菌群及能量代谢平衡均存在异常；GLP-1可以促进下丘脑GnRH神经元Kiss1表达。据此提出假说：肠道菌群可能通过GLP-1信号影响糖代谢，实现与Kiss1/Gpr54的交互作用，进而改变GnRH神经元的发育、分化以及功能稳态参与性发育进程的调控。本项目拟通过性腺摘除及菌群移植小鼠研究肠道菌群与Kiss1/Gpr54系统的交互作用；以GLP-1、利拉鲁肽及菌群代谢产物刺激GT1-7细胞，研究肠道微生物对GnRH神经元功能影响的分子机制。研究可为从肠道微生态及代谢紊乱角度干预及调控性发育提供基础。

Kiss1/Gpr54 systems in the ARC are key components of the HPG axis, have been demonstrated as targets of the most important regulators of the generation of pulsatile GnRH secretion. However, most of the abnormal puberty onset cannot be accounted for the genetic and transcriptional abnormalities of Kiss1/Gpr54 genes. Kisspeptin neurons Kiss1 action in ARC is dependent on energy status and unmasking metabolic factors responsible for modulating ARC Kiss1/Gpr54 neurons remains one of neuroendocrinology’s most fundamental problems. One possible factor is glucagon-like peptide 1 (GLP-1), which can promote kiss1 expression in vivo an in vitro. Our previous researches and preliminary studies have revealed that besides transcription factors such as EAP1 and CUX1, Kiss1/Gpr54 activation was also regulated by nutritional metabolism. We also observed significant metabolomics and microbiomics changes in the girls with precocious puberty, which suggests that the development of sex may involve an alteration in symbiotic gut microbial composition. While, besides regulation of sex development, Kiss1/Gpr54 also plays an important role in the regulation of glucose metabolism. So we hypothesize that via regulating carbohydrate and energy metabolism, through GLP-1/GLP-1r pathways the interaction between gut microbiome and Kiss1/Gpr54 system plays a major role in maintaining hypothalamic pituitary gonadal axis homeostasis. To establish the hypothesis, we will investigate the interaction between microbes and Kiss1/Gpr54 system by comparing germfree, gonadectomy and hormone replaced mice. To investigate the effects of microbes on the signaling pathways that may be involved in GnRH secretion from the hypothalamus neurons, the GT1–7 cell line, an in vitro model for GnRH-secreting neurons being used, we will examine signal transduction pathways affected by microbes associated carbohydrate metabolism. These results will provide new evidence for understanding of the mechanism of the interplay between Kiss1/GPR54 system and gut microbes in the mechanism of puberty onset and hold great promise for future novel pathways of intervention in sexual development disease.