Astrocytes may be more than just the brain’s ‘housekeepers.’ While largely known for their role in supporting neuron structure and maintaining the highly selective blood-brain barrier, these cells of the brain are now emerging as critical contributors to the control network of the human reproductive system as well.
A recent study reveals that astrocytes may play a variety of roles beyond their traditionally known functions, especially through their interactions with kisspeptin, a protein best known for its role in triggering the release of reproductive hormones. Kisspeptin is primarily produced in a region of the brain called the hypothalamus, which controls essential functions like hunger, sleep, and hormone release. There, kisspeptin works to stimulate the release of gonadotropin-releasing hormone (GnRH), which in turn travels to the anterior pituitary to prompt the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Together, these hormones regulate the production of gametes—eggs in females and sperm in males—and control the secretion of sex hormones from the gonads, supporting fertility and reproductive health throughout life.
Within the scientific literature, kisspeptin has mainly been viewed as having a neuron-specific role in the brain, primarily working with the GnRH neurons. However, new findings from the study reveal that astrocytes are also direct targets of kisspeptin. This discovery sheds new light on the involvement of non-neuronal cells in regulating reproductive systems, marking the first-ever identification of non-neuronal cells directly influencing reproductive and metabolic regulation.
Astrocytic Kisspeptin: A Buffering System for GnRH Neurons?
The study is a collaboration between several European universities and the lab of Tamas Horvath, the Jean and David W. Wallace Professor of Comparative Medicine at the Yale School of Medicine. The collaboration began when a research team at the Instituto Maimónides de Investigación Biomédica de Córdoba in Spain reached out to the Horvath Lab to learn more about the anatomy of the hypothalamus. “We focused on exploring how this knowledge could be leveraged to study kisspeptin-related signaling pathways,” Horvath said.
The study commenced using mice engineered to lack kisspeptin to explore the potential role of astrocytes in kisspeptin signaling. In this mouse model, researchers observed an increase in the interaction between astrocytes and GnRH neurons. This suggested that, under normal conditions, kisspeptin likely plays a key role in regulating the interaction between these cells. With the loss of kisspeptin signaling, the astrocyte-GnRH neuron interface observed may have adapted as a compensatory mechanism to restore normal GnRH activity.
Thus, this astrocytic pathway may function as a self-regulatory loop, controlling GnRH neuron stimulation in response to kisspeptin. In a different mouse model where the genes for kisspeptin receptors (Kiss1r) were removed from astrocytes, researchers observed an increase in the expression of certain genes involved in prostaglandin E2 (PGE2) synthesis. Since PGE2 is a potent activator of GnRH neurons, this suggests that kisspeptin signaling in astrocytes plays a role in regulating GnRH secretion through PGE2 production. Without this regulation, the GnRH neurons become more susceptible to overactivation, disrupting the normal rhythm of reproductive hormone release.
Decoding Astrocyte Involvement: A Proteomic Breakthrough
Next, the team employed advanced proteomic techniques, which analyze proteins and their interactions on a large scale, to further investigate the effects of astrocytic kisspeptin. They used protein-protein interaction networks, which map interactions between various interrelated proteins, and generated gene ontology graphs to visually represent the relationships between genes and their associated biological functions. These methods allowed the researchers to compare the hypothalamic protein profiles of mice before and after a controlled kisspeptin dose. Their analysis identified several clusters of proteins impacted by kisspeptin, including markers for astrocytes, such as glial fibrillary acidic protein. This surprising discovery suggested that kisspeptin targets astrocytes in addition to neurons, particularly in regions densely populated by GnRH neurons.
However, proteomics alone were not sufficient to confirm kisspeptin-related actions within astrocytes. Further functional investigations confirmed that astrocytes express Kiss1r in several reproductive brain regions, such as the hypothalamus, which are known to play key roles in reproductive regulation. Using both in vitro and in vivo models, the team demonstrated that the binding of kisspeptin to these receptors activates key signaling pathways within astrocytes, including the phosphorylation of extracellular signal-regulated kinases (ERK) 1/2 and protein kinase B—two proteins critical for cell growth and survival pathways. This evidence of functional kisspeptin receptors in astrocytes suggests the existence of an astrocyte-specific kisspeptin signaling pathway within the reproductive brain.
Physiological Impacts: From Reproduction to Metabolism
Once a connection between astrocytes and kisspeptin was established, the next step was to discern the functional significance of these astrocytic pathways. To accomplish this, researchers studied the mouse model where Kiss1r was removed from astrocytes. The group observed that female mice lacking kisspeptin receptors in astrocytes displayed irregular estrous cycles—the mouse analog to menstrual cycles. In addition, the mice had modified LH secretory profiles. High-fat diets, which typically accelerate puberty and alter reproductive function in control animals, did not impact puberty onset in the female Kiss1r-knockout mice, indicating that kisspeptin signaling in astrocytes may normally play a key role in adapting reproductive function to metabolic changes. Horvath believes that the underlying reason behind these irregularities lies in the coordination of the hypothalamus. “Affecting the hypothalamus [through kisspeptin-signalling in astrocytes] has the ability to impact the coordination of various homeostatic functions, including metabolism, as well as higher cognitive functions,” Horvath said.
Astrocytic kisspeptin signaling also seemed to influence metabolic regulation. The researchers found that in male mice, conditional knockout of astrocytic kisspeptin receptors resulted in a marked improvement in glucose tolerance, which is the body’s ability to regulate blood sugar levels after consuming carbohydrates. Based on this, the researchers predicted that kisspeptin signaling may promote glucose intolerance, or a reduced ability to manage blood sugar levels effectively. While promoting glucose intolerance seems counterproductive, it may actually be part of a larger metabolic strategy.Glucose intolerance signals to the body that it is under metabolic stress or that it is not efficiently using energy. This encourages the body to prioritize energy balance over reproductive function until conditions improve, serving as a protective mechanism.
This observation aligns with recent literature that astrocytes help regulate energy homeostasis, responding to changes in diet and metabolic state. The kisspeptin-astrocyte pathway, therefore, could be a bridge linking reproductive health with metabolic balance, adjusting reproductive timing and function based on the body’s nutritional status.
Future Directions and Therapeutic Potential
This discovery of astrocytic involvement in kisspeptin signaling challenges the long-held neuron-centric view of reproductive control, adding a new level of complexity to our understanding of the regulation of fertility and metabolism. It also raises new questions about whether other non-neuronal brain cells might interact similarly with GnRH neurons.
The researchers plan to expand the research project in two primary directions. Horvath described a general goal to keep exploring how different brain cells interact under varying conditions, including how these interactions may influence changes in brain plasticity—the brain’s ability to reorganize and adapt its structure and function in response to new experiences, learning, or injury.
The team is also keen to explore the therapeutic implications of their findings. “We want to look at testing to see if our results remain consistent with humans,” Horvath said. If these fundamental results can be extrapolated to humans, they would offer a potential target for modulating reproductive health in the context of metabolic dysfunction. Drugs designed to selectively inhibit or activate kisspeptin signaling in astrocytes would provide a novel manner of fine-tuning reproductive function without directly affecting neurons, minimizing potential side effects. Additionally, interventions targeting this pathway might offer new ways to manage conditions like polycystic ovary syndrome, which is often linked to insulin resistance and metabolic dysfunction. Ultimately, this research could pave the way for more precise, targeted approaches to address reproductive health challenges and metabolic disorders, potentially delaying age-related fertility decline.