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GLP-1RA Ameliorates Polycystic Ovary Syndrome via Hypothalamic RASA1/AKT: A Novel pathway Linking Hyperandrogenism to GnRH Dysregulation

ABSTRACT: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and hypothalamic-pituitary-gonadal (HPG) axis dysregulation involving gonadotropin-releasing hormone (GnRH) hyperactivity. While glucagon-like peptide-1 receptor agonists (GLP-1RAs) show therapeutic promise in PCOS, their central regulation mechanisms remain unknown. Here, we demonstrate that GLP-1RA improves follicular maturation in PCOS via hypothalamic RASA1-dependent modulation of GnRH secretion. Based on our letrozole-induced PCOS rats, GLP-1RA was shown to restore hormonal homeostasis by normalizing testosterone, suppressing luteinizing hormone, and reinstating estrous cyclicity alongside ovarian recovery. Proteomics analysis revealed a substantial recovery from hyperandrogenism-induced hypothalamic dysregulation after GLP-1RA therapy. Landscapes of PCOS and GLP-1RA hypothalamic perturbations were systematically drawn. Crucially, subsequent network analysis identified RASA1-GnRH axis as a core axis underpins GLP-1RA related pharmacological rescue of PCOS hypothalamus. Bidirectional genetic perturbations of RASA1 in GnRH neurons rigorously confirmed RASA1's regulation over GnRH synthesis, as well as the mediating role of Ras/AKT in this pathway. Notably, the modulation of both RASA1 and Akt effectively counteracted testosterone-induced GnRH hypersecretion and reversed GLP-1RA treatment-mediated GnRH suppression, thereby fully establishing GLP-1RA’s pharmacological mechanism through RASA1-Ras/Akt-GnRH signaling axis. Our study represented the first investigation into the hypothalamic molecular mechanism by which GLP-1RA improves PCOS, highlighting RASA1 as a critical mediator of HPG axis in the female reproductive systems. The discovery of novel target in central control would serve as a promising therapeutic strategy for PCOS reproductive improvement beyond metabolic treatment.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Linlin Yang

PROVIDER: PXD064291 | iProX | Mon May 26 00:00:00 BST 2025

REPOSITORIES: iProX

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Project description:This a model from the article: Modeling robust oscillatory behavior of the hypothalamic-pituitary-adrenal axis. Kyrylov V, Severyanova LA, Vieira A. IEEE Trans Biomed Eng. 2005 Dec;52(12):1977-83. 16366221 , Abstract: A mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis of the human endocrine system is proposed. This new model provides an improvement over previous models by introducing two nonlinear factors with physiological relevance: 1) a limit to gland size; 2) rejection of negative hormone concentrations. The result is that the new model is by far the most robust; e.g., it can tolerate at least -50% and +100% perturbations to any of its parameters. This high degree of robustness allows one, for the first time, to model features of the system such as circadian rhythm and response to hormone injections. In addition, relative to its closest predecessor, the model is simpler; it contains only about half of the parameters, and yet achieves more functions. The new model provides opportunities for teaching endocrinology within a biological or medical school context; it may also have applications in modeling and studying HPA axis disorders, for example, related to gland size dynamics, abnormal hormone levels, or stress influences. This model was taken from the CellML repository and automatically converted to SBML. The original model was: Kyrylov V, Severyanova LA, Vieira A. (2005) - version02 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@aukland.ac.nz The University of Auckland The Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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GLP-1RA Ameliorates Polycystic Ovary Syndrome via Hypothalamic RASA1/AKT: A Novel pathway Linking Hyperandrogenism to GnRH Dysregulation

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