Multi-omic dissection of reversible and persistent molecular alterations in diet-induced obesity
Year: 2026
Type: preprint
Abstract: Diet-induced obesity drives broad molecular remodeling across host and microbial systems, but why lifestyle intervention reverses some of these alterations while others persist remains unclear. To address this, we performed a multi-omic characterization of diet-induced obese mice after a combined nutritional and exercise intervention, integrating liver transcriptomics, epigenomics, metabolomics and metallomics with gut metagenomics and metallomics. Multi-omics factor analysis resolved two dominant axes of variation. The first captured a broadly reversible response (∼72% of altered variables), restored by dietary restriction and exercise, involving coordinated remodeling of hepatic metal homeostasis, epigenetic regulation, and immune and cell-turnover pathways. The second comprised persistent alterations resistant to intervention and driven primarily by microbial functional profiles: notably, functional diversity remained reduced despite substantial taxonomic recovery. Using germ-free mice to define the microbiota-responsive hepatic space, we found that a significant fraction of the persistent liver features fell within it, enriched in lipid metabolism (PPAR signaling, steroid and cholesterol biosynthesis, peroxisomal activity) and retinol metabolism. Sequential correlation analysis traced these changes to the loss of specific low-abundance taxa and their biosynthetic capacities, particularly vitamin (folate, biotin, cobalamin, pantothenate, thiamine) and cofactor metabolism, implicating microbiota-derived vitamin metabolism in sustained hepatic dysfunction. Cobalt was the sole essential element that remained persistently dysregulated and tracked dietary cobalt content, suggesting a diet– microbiota route to the persistent phenotype. These findings establish a dual regulatory framework in which metabolic plasticity is governed by reversible host-intrinsic and persistent microbiota-dependent processes, providing a systems-level explanation for obesogenic memory.
Institutions: Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Universitat Rovira i Virgili, Institut d'Investigació Biomédica de Bellvitge, Universitat de Barcelona, Institut de Recerca Biomèdica Catalunya Sud, Hospital Universitari Sant Joan de Reus, University of Augsburg, Heidelberg University, Ludwig-Maximilians-Universität München, Barcelona Supercomputing Center, AgroParisTech, Université Paris-Saclay, Microbiologie de l’alimentation au service de la santé, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Centro de Investigación Biomédica en Red
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1401168639, G2198857690, G2309174360, G2660406951, G3288897321, G3448680423, G3480869486, G3518538256, Chromatin and Metabolism Chromatin-metabolism interactions as targets for healthy living, European Advanced infraStructure for Innovative Genomics, G4228227490, G4325654541, G5080475149, G5320413469, G6033112984, G6039332712, Estudio integrativo y traslacional de la desregulación metabólica debida a la obesidad. Repercusiones sobre la plasticidad del tejido adiposo blanco, G7084143925, G7102968246, G7245015376, G7603373443, G7676764825, G8488971488, G8575141037, G8920660035
OpenAlex ID: W7212230300