Integration of transcriptomic data in a genome-scale metabolic model to investigate the link between obesity and...

Obesity is a complex disorder associated with an increased risk of developing several comorbid chronic diseases, including postmenopausal breast cancer. Although many studies have investigated this issue, the link between body weight and either risk or poor outcome of breast cancer is still to characterize. Systems biology approaches, based on the integration of multiscale models and data from a wide variety of sources, are particularly suitable for investigating the underlying molecular mechanisms of complex diseases. In this scenario, GEnome-scale metabolic Models (GEMs) are a valuable tool, since they represent the metabolic structure of cells and provide a functional scaffold for simulating and quantifying metabolic fluxes in living organisms through constraint-based mathematical methods. The integration of omics data into the structural information described by GEMs allows to build more accurate descriptions of metabolic states.

In this work, we exploited gene expression data of postmenopausal breast cancer obese and lean patients to simulate a curated GEM of the human adipocyte, available in the Human Metabolic Atlas database. To this aim, we used a published algorithm which exploits a data-driven approach to overcome the limitation of defining a single objective function to simulate the model. The flux solutions were used to build condition-specific graphs to visualise and investigate the reaction networks and their properties. In particular, we performed a network topology differential analysis to search for pattern differences and identify the principal reactions associated with significant changes across the two conditions under study.

Metabolic network models represent an important source to study the metabolic phenotype of an organism in different conditions. Here we demonstrate the importance of exploiting Next Generation Sequencing data to perform condition-specific GEM analyses. In particular, we show that the qualitative and quantitative assessment of metabolic fluxes modulated by gene expression data provides a valuable method for investigating the mechanisms associated with the phenotype under study, and can foster our interpretation of biological phenomena.