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

ABSTRACT: Polycystic ovary syndrome (PCOS) is a heterogeneous condition, of polyhedric pathogenesis and clinical presentation, defined by oligo-/anovulation, hyperandrogenism and/or polycystic ovaries. Metabolic complications are highly common also in patients suffering PCOS, including obesity, insulin resistance and type-2 diabetes, which severely compromise the clinical course of affected women. Yet, therapeutic options for PCOS remain mostly symptomatic and of limited efficacy for improving both metabolic and reproductive alterations. We report herein the hormonal, metabolic and gonadal responses to different GLP1-based multi-agonists, namely GLP1/Estrogen (GLP1/E), GLP1/GIP and GLP1/GIP/Glucagon, in two murine models of PCOS, with variable penetrance of metabolic and reproductive traits, and their comparison with metformin. Our data illustrate the superior efficacy of the di-agonist, GLP1/E, vs. other multi-agonists and metformin in the management of the metabolic complications of PCOS; GLP1/E was able to ameliorate also ovarian cyclicity in an ovulatory model of PCOS, without direct estrogenic uterotrophic effects. In keeping with GLP1-mediated brain targeting, label-free, quantitative proteomics revealed 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.

INSTRUMENT(S): Bruker Daltonics timsTOF series

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Víctor Serrano López  

LAB HEAD: Manuel Tena Sempere

PROVIDER: PXD044134 | Pride | 2024-10-02

REPOSITORIES: Pride