Superior metabolic improvement of polycystic ovary syndrome traits after GLP1-based multi-agonist therapy
: Sánchez-Garrido, Miguel A.; Serrano-López, Víctor; Ruiz-Pino, Francisco; Vázquez, María Jesús; Rodríguez-Martín, Andrea; Torres, Encarnación; Velasco, Inmaculada; Rodríguez, Ana Belén; Chicano-Gálvez, Eduardo; Mora-Ortiz, Marina; Ohlsson, Claes; Poutanen, Matti; Pinilla, Leonor; Gaytán, Francisco; Douros, Jonathan D.; Yang, Bin; Müller, Timo D.; DiMarchi, Richard D.; Tschöp, Matthias H.; Finan, Brian; Tena-Sempere, Manuel
Publisher: Springer Science and Business Media LLC
: 2024
: Nature Communications
: Nature Communications
: 8498
: 15
: 1
: 2041-1723
DOI: https://doi.org/10.1038/s41467-024-52898-y
: https://doi.org/10.1038/s41467-024-52898-y
: https://research.utu.fi/converis/portal/detail/Publication/458453579
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.
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This work was supported by grants BFU2017-83934-P, PID2020-118660GB-I00, and PID2021-126915 OA-I00 (Agencia Estatal de Investigación, Spain; co-funded with EU funds from FEDER Program); project PIE14-00005 (Flexi-Met, Instituto de Salud Carlos III, Ministerio de Sanidad, Spain); Projects P12-FQM-01943 and P18-RT-4093 (Junta de Andalucía, Spain), Project 1254821 (University of Cordoba-FEDER); EU research contract GAP-2014-655232; and Miguel Servet research contract CP20/00080 (Instituto de Salud Carlos III; Ministerio de Sanidad, Spain). TDM was supported for this work by funding from the German Research Foundation (DFG TRR296, TRR152, SFB1123, and GRK 2816/1), the German Center for Diabetes Research (DZD e.V.) and the European Research Council ERC-CoG Trusted no.101044445. CIBER is an initiative of Instituto de Salud Carlos III (Ministerio de Sanidad, Spain).
