Multi-omic dissection of reversible and persistent molecular alterations in diet-induced obesity
- 1Universitat Rovira i Virgili
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.
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BibTeX
@misc{rofes2026multiomic,
title = {{Multi-omic dissection of reversible and persistent molecular alterations in diet-induced obesity}},
author = {J. Rofes and J. Miro-Blanch and P. Gama-Perez and J. Capellades and C. M. Heyer and I. Forne and L. Santus and A. Balvay and C. Maudet and S. Rabot and B. Carbonetto and P. Gonzalez-Torres and M. Mele and A. Imhof and M. Schlesner and P. M. Garcia-Roves and O. Yanes},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.08.749914},
url = {https://www.biorxiv.org/content/10.64898/2026.09.08.749914v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Multi-omic dissection of reversible and persistent molecular alterations in diet-induced obesity
AU - J. Rofes
AU - J. Miro-Blanch
AU - P. Gama-Perez
AU - J. Capellades
AU - C. M. Heyer
AU - I. Forne
AU - L. Santus
AU - A. Balvay
AU - C. Maudet
AU - S. Rabot
AU - B. Carbonetto
AU - P. Gonzalez-Torres
AU - M. Mele
AU - A. Imhof
AU - M. Schlesner
AU - P. M. Garcia-Roves
AU - O. Yanes
PY - 2026
DA - 2026/09/08
PB - bioRxiv
DO - 10.64898/2026.09.08.749914
UR - https://www.biorxiv.org/content/10.64898/2026.09.08.749914v1
AB - 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.
ER -