Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy

Miguel A. Sánchez-Garrido (), Víctor Serrano-López, Francisco Ruiz-Pino, María Jesús Vázquez, Andrea Rodríguez-Martín, Encarnación Torres, Inmaculada Velasco, Ana Belén Rodríguez, Eduardo Chicano-Gálvez, Marina Mora-Ortiz, Claes Ohlsson, Matti Poutanen, Leonor Pinilla, Francisco Gaytán, Jonathan D. Douros, Bin Yang, Timo D. Müller, Richard D. DiMarchi, Matthias H. Tschöp, Brian Finan and Manuel Tena-Sempere ()
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Miguel A. Sánchez-Garrido: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Víctor Serrano-López: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Francisco Ruiz-Pino: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
María Jesús Vázquez: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Andrea Rodríguez-Martín: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Encarnación Torres: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Inmaculada Velasco: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Ana Belén Rodríguez: University of Córdoba
Eduardo Chicano-Gálvez: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Marina Mora-Ortiz: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Claes Ohlsson: University of Gothenburg
Matti Poutanen: University of Gothenburg
Leonor Pinilla: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Francisco Gaytán: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)
Jonathan D. Douros: Novo Nordisk Research Center Indianapolis
Bin Yang: Novo Nordisk Research Center Indianapolis
Timo D. Müller: Helmholtz Zentrum München
Richard D. DiMarchi: Indiana University
Matthias H. Tschöp: Helmholtz Zentrum München
Brian Finan: Novo Nordisk Research Center Indianapolis
Manuel Tena-Sempere: Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Polycystic ovary syndrome (PCOS) is a heterogeneous condition, defined by oligo-/anovulation, hyper-androgenism and/or polycystic ovaries. Metabolic complications are common in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options remain mostly symptomatic and of limited efficacy for the metabolic and reproductive alterations of PCOS. We report here the hormonal, metabolic and gonadal responses to the glucagon-like peptide-1 (GLP1)-based multi-agonists, GLP1/Estrogen (GLP1/E), GLP1/gastric inhibitory peptide (GLP1/GIP) and GLP1/GIP/Glucagon, in two mouse PCOS models, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of GLP1/E vs. other multi-agonists and metformin in the management of metabolic complications of PCOS; GLP1/E ameliorates also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, quantitative proteomics reveals changes in common and distinct hypothalamic pathways in response to GLP1/E between the two PCOS models, as basis for differential efficiency. Altogether, our data set the basis for the use of GLP1-based multi-agonists, and particularly GLP1/E, in the personalized management of PCOS.

Date: 2024
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DOI: 10.1038/s41467-024-52898-y

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