Department of Zoology, Goa University, Taleigao Plateau, Goa, India.
Department of Biological Sciences, BITS Pilani, K K Birla Goa Campus, Zuarinagar, Goa, India.
Reprod Sci. 2022 Sep;29(9):2546-2564. doi: 10.1007/s43032-021-00814-w. Epub 2022 Feb 9.
GnRH-I produced by hypothalamic neurosecretory cells is considered a master regulator of mammalian reproduction. Although GnRH-I transcription is well studied, the effect of ageing on transcriptional regulation of GnRH-I has not yet been explored. Here, we elucidate the effects of ageing on the metabolic environment like lactate level and TNF-α and how these affect GnRH-I transcription. Using pathway analysis of transcriptomic data, we found that lactate is upregulated in ageing astrocytes due to the downregulation of cellular respiration pathways possibly resulting in greater pyruvate concentration for lactate production. This lactate could then be shuttled into neurons where it would affect GnRH-I transcription. We showed that supra-physiological level of lactate in young mouse brain can mimic metabolic disturbances in the old brain and cause downregulation in GnRH-I transcription at a young age. In particular, we found upregulation of GnRH-I repressors in the young brain treated with high levels of lactate similar to old brain. Hence, this confirmed that aged metabolic environment can affect GnRH-I transcription even in the young brain. Further downstream analysis using the TRUST database showed NF-Kb signalling which lies downstream of both lactate and TNF-α as being capable of upregulating GnRH-I repressors. Since NF-Kb signalling has been shown in our study as well as others to be induced by TNF-α during ageing, it is likely that GnRH-I transcriptional regulation is mediated through these pathways. Thus, we formed a model for explaining the downregulation of GnRH-I transcription during ageing through differential expression of its TFs in an aged metabolic environment.
下丘脑神经分泌细胞产生的 GnRH-I 被认为是哺乳动物生殖的主要调节剂。尽管 GnRH-I 的转录已得到很好的研究，但年龄对 GnRH-I 转录的调节作用尚未得到探索。在这里，我们阐明了年龄对代谢环境（如乳酸水平和 TNF-α）的影响，以及这些环境如何影响 GnRH-I 的转录。通过对转录组数据的途径分析，我们发现衰老的星形胶质细胞中乳酸上调，这可能是由于细胞呼吸途径的下调，导致更多的丙酮酸用于乳酸生成。这种乳酸可以被转运到神经元中，从而影响 GnRH-I 的转录。我们表明，年轻小鼠大脑中超生理水平的乳酸可以模拟老年大脑的代谢紊乱，并导致 GnRH-I 转录在年轻时下调。特别是，我们发现年轻大脑中用高浓度乳酸处理后 GnRH-I 抑制剂的上调与老年大脑相似。因此，这证实了衰老的代谢环境即使在年轻的大脑中也能影响 GnRH-I 的转录。使用 TRUST 数据库进行的进一步下游分析表明，NF-Kb 信号通路位于乳酸和 TNF-α的下游，能够上调 GnRH-I 抑制剂。由于 NF-Kb 信号通路在我们的研究以及其他研究中均显示在衰老过程中由 TNF-α诱导，因此 GnRH-I 的转录调节可能是通过这些途径介导的。因此，我们形成了一个模型，解释了在衰老代谢环境中，由于其 TF 在年龄上的差异表达， GnRH-I 转录的下调。
