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.
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Research Article Endocrinology Reproductive biology

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

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Figure 4

Kiss1r expression in astrocytes from adult mice isolated by FACS.

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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.