Kisspeptin signaling in astrocytes modulates the reproductive axis
Encarnacion Torres, … , Manuel Tena-Sempere, Antonio Romero-Ruiz
Encarnacion Torres, … , Manuel Tena-Sempere, Antonio Romero-Ruiz
Published June 11, 2024
Citation Information: J Clin Invest. 2024;134(15):e172908. https://doi.org/10.1172/JCI172908.
View: Text | PDF
Research Article Endocrinology Reproductive biology Article has an altmetric score of 29

Kisspeptin signaling in astrocytes modulates the reproductive axis

Abstract

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.

Authors

Encarnacion Torres, Giuliana Pellegrino, Melissa Granados-Rodríguez, Antonio C. Fuentes-Fayos, Inmaculada Velasco, Adrian Coutteau-Robles, Amandine Legrand, Marya Shanabrough, Cecilia Perdices-Lopez, Silvia Leon, Shel H. Yeo, Stephen M. Manchishi, Maria J. Sánchez-Tapia, Victor M. Navarro, Rafael Pineda, Juan Roa, Frederick Naftolin, Jesús Argente, Raúl M. Luque, Julie A. Chowen, Tamas L. Horvath, Vincent Prevot, Ariane Sharif, William H. Colledge, Manuel Tena-Sempere, Antonio Romero-Ruiz

×

Figure 4

Kiss1r expression in astrocytes from adult mice isolated by FACS.

Options: View larger image (or click on image) Download as PowerPoint
Kiss1r expression in astrocytes from adult mice isolated by FACS. (A) Ga...
(A) Gating strategy for astrocyte isolation by FACS. The 2 plots in the left represent cells incubated with the control isotype; the 2 plots in the right represent cells incubated with the anti-ACSA-2-PE antibody. (B) Real-time PCR of astroglial [Gfap, Glast, Connexin-43 (Cx43)], neuronal (Elavl3, RBFox3), microglial (Aif1), and endothelial (CD31) genes in FACS-sorted positive and negative fractions of the MBH of female mice, used for validation purposes. (C) Real-time PCR analysis of Kiss1r in FACS-sorted positive and negative fractions obtained from 3 brain areas (POA, MBH, and cortex [CTX]) of adult male and female (diestrus) mice. Expression data segregated by sex (females, left panel; males, right panel) are presented. Sex-aggregated data, divided per brain region, are displayed in D. n = 6 animals per sex. Values in the positive fraction are expressed relative to negative fraction values, set at 1. Data are the mean ± SEM. Statistical significance was determined by Student’s t test in B: *P < 0.05; **P < 0.01, versus corresponding negative fraction; and by 2-way ANOVA followed by Bonferroni’s post hoc test for regional and sex analyses in C and D: *P < 0.05; **P < 0.01 versus negative fraction. Note that of the 36 positive fractions (3 regions × 2 sexes × 6 animals per group) tested, Kiss1r expression was readily detectable in 33, with a mean Ct value of 21.9.