Multi-Omics Factor Analysis v2 (MOFA+) reveals specific co-variation patterns in women with PMOS that are strongly influenced by obesity

Abstract STUDY QUESTION What are the mechanisms underlying the complex interactions between polyendocrine metabolic ovarian syndrome (PMOS) and obesity as studied by a multi-omics integration approach? SUMMARY ANSWER Multi-Omics Factor Analysis v2 (MOFA+) suggested that PMOS was characterized by an androgen-driven metabolic reprogramming in which sexual dimorphism was reshaped in an obesity- and omics-specific manner, consisting of strong associations of proinflammatory proteins and adipokines with gut microbiota genera and metabolomics variables that were amplified by obesity. WHAT IS KNOWN ALREADY PMOS is a common metabolic-endocrine disorder in which androgen excess, weight excess and obesity complex interactions define a particularly unfavorable cardiometabolic phenotype. STUDY DESIGN, SIZE, DURATION Cross-sectional study with 2 control groups involving 46 Caucasian young adults, conducted at an Academic Hospital in Madrid, Spain. PARTICIPANTS/MATERIALS, SETTING, METHODS We recruited 15 women with PMOS, 16 healthy control women, and 15 control men of similar mean age and BMI. Participants were further grouped into non-obese (BMI < 30 kg/m²) or obese (BMI ≥ 30 kg/m²) subjects. We integrated serum metabolomics and circulating proteins with gut microbiota composition, using MOFA+. MAIN RESULTS AND THE ROLE OF CHANCE MOFA+ identified five latent factors explaining the main sources of variation across omics layers. Results showed sexual dimorphism in an omics- and obesity-specific manner: the metabolomics profile presented sexual dimorphism in non-obese individuals, whereas circulating proteins and gut microbiota differed between women with or without PMOS and men only in obese subjects. Correlation analyses revealed a global weakening of associations in men, particularly among metabolites, a reinforcement of protein-related associations with obesity, and a distinct PMOS-specific pattern characterized by strengthened correlations within and between gut microbiota and proteomic features. Women with PMOS exhibited the strongest metabolomics-proteomics correlations, further exacerbated by obesity. LIMITATIONS, REASONS FOR CAUTION The relatively small sample size of our study might have missed relevant associations that could have reached statistical significance in larger samples. Also, we only included women with hyperandrogenic phenotypes of PMOS. Hence, our results may not apply to non-hyperandrogenic phenotypes of the syndrome. WIDER IMPLICATIONS OF THE FINDINGS PMOS showed a metabolic profile similar to that of obesity even in the absence of excess weight, supporting the concept that adipose tissue dysfunction, proinflammatory proteins and adipokines, rather than fat mass excess per se, was a central driver of the metabolic disturbances of the syndrome. Altogether, these findings highlight the complex interplay between androgen excess, adiposity and host–microbiota interactions, and provide a systems-level framework that may facilitate the identification of novel biomarkers and targeted therapeutic strategies in PMOS. Also, these findings highlight the importance of considering sex, sex hormones and obesity-specific contexts in biomarker discovery and mechanistic studies. FUNDING This research was funded by Instituto de Salud Carlos III grants PI11/0357, PI18/01122 and PI21/00116, and co-funded by the European Union. Francisco Garcia-Garcia was supported by CIAICO/2023/149 funded by the Consellería de Educación, Cultura y Universidades de la Generalitat Valenciana, and PID2021-124430OA-I00 funded by MICIU/AEI/10.13039/501100011033 and by ERDF/EU. CIBERDEM and IRYCIS are also initiatives of Instituto de Salud Carlos III. DISCLOSURES The funding organizations played no role in the study design; collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the report for publication. The Authors have no competing interests to disclose TRIAL REGISTRATION NUMBER N/A