Kisspeptin signaling in astrocytes modulates the reproductive axis

• Published in: The Journal of clinical investigation Vol. 134; no. 15; pp. 1 - 16
• Main Authors: Torres, Encarnacion, Pellegrino, Giuliana, Granados-Rodríguez, Melissa, Fuentes-Fayos, Antonio C, Velasco, Inmaculada, Coutteau-Robles, Adrian, Legrand, Amandine, Shanabrough, Marya, Perdices-Lopez, Cecilia, Leon, Silvia, Yeo, Shel H, Manchishi, Stephen M, Sánchez-Tapia, Maria J, Navarro, Victor M, Pineda, Rafael, Roa, Juan, Naftolin, Frederick, Argente, Jesús, Luque, Raúl M, Chowen, Julie A, Horvath, Tamas L, Prevot, Vincent, Sharif, Ariane, Colledge, William H, Tena-Sempere, Manuel, Romero-Ruiz, Antonio
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2024
• Subjects: Analysis; Animals; Astrocytes; Astrocytes - metabolism; Dinoprostone - metabolism; Estrus cycle; Female; Gene expression; Genes; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - genetics; Gonadotropin-Releasing Hormone - metabolism; High fat diet; Humans; Hypothalamus; Hypothalamus - metabolism; Influence; Intracellular signalling; Kiss1 protein; Kisspeptins - genetics; Kisspeptins - metabolism; Luteinizing hormone; Male; Metabolism; Mice; Mice, Knockout; Neuromodulation; Neuronal-glial interactions; Neurons; Neurons - metabolism; Ontology; Physiological aspects; Prostaglandin E2; Protein interaction; Protein-protein interactions; Proteins; Proteomics; Puberty; Rats; Receptors, Kisspeptin-1 - genetics; Receptors, Kisspeptin-1 - metabolism; Reproduction; S100 Calcium Binding Protein beta Subunit - genetics; S100 Calcium Binding Protein beta Subunit - metabolism; Sexes; Signal Transduction; Steroids; Spain; Neuroendocrine regulation; Fertility; Reproductive biochemistry; Endocrinology; Reproductive biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI172908

Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-β occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.