ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This study uses a combination of proteomics and murine transgenics to identify the role of Kisspeptin signalling in astrocytes and how it impacts the reproductive axis.

Kisspeptin, a neuropeptide, is essential for regulating the hypothalamic-pituitary-gonadal (HPG) axis, which controls reproduction by acting on GnRH neurons. While most studies have focused on GnRH neurons as the primary mediators of kisspeptin signalling and function, this study highlights astrocytes, a type of glial cell in the brain, as an important modulator in this process. The researchers first identify upon stimulation of hypothalamic cells with Kisspeptin, the upregulation of astrocyte markers such as GFAP, and APP using label-free proteomics, suggesting that Kisspeptin has a function in astrocytes. They then show the expression of the Kisspeptin receptor (Kiss1r) in astrocytes and show active signalling resulting in increased phosphorylation of ERK1/2. To further elucidate the role of Kisspeptin in astrocytes, the authors elegantly delete the Kiss1r solely in the astrocytes by using an astrocyte-specific Cre line generating the G-KiR-KO murine transgenic. Male and female mice lacking Kiss1r in astrocytes display normal pubertal timing, although response to LH was increased in female mice. Deletion of Kiss1r resulted in upregulation of PGE2 which is a major upregulator of GnRH neurons. Hence, Kisspeptin action in astrocytes seems to be modulatory to fine-tune GnRH neuron’s function but its depletion in astrocytes is insufficient to cause hypogonadism. The authors identify that G-KiR-KO mice under a high-fat diet (HFD) display disturbed LH pulses with lengthening of oestrus cycles indicating that Kisspeptin in astrocytes modulates the deleterious effects of HFD on the reproductive system.

In conclusion, this study shows that kisspeptin receptors on astrocytes can influence the release of gonadotropin-releasing hormone (GnRH), the key hormone initiating the reproductive cycle. This discovery adds another layer of complexity to our understanding of the reproductive axis, suggesting that astrocytes are not just passive support cells but active participants in neuroendocrine functions. The discovery of kisspeptin’s interaction with astrocytes in modulating the reproductive axis challenges the long-standing neuron-centric view of reproductive GnRH regulation. These findings add to the growing body of evidence that glial cells, particularly astrocytes, are more than just supportive structures in the brain.