Distinct gene signatures of human intermuscular adipose tissue expansion visualized by spatial transcriptomics in mice

Intermuscular adipose tissue (IMAT) expansion is closely associated with cardiometabolic disease (CMD), yet its cellular organization and regulatory mechanisms remain poorly defined. Using bulk transcriptomics on human IMAT, we identified a distinct gene signature and functional regulators including adipogenic transcription factor early B-cell factor 2 (EBF2). By mapping this human signature to the spatial transcriptome of IMAT from mice with CMD, we unraveled discrete stromal niches surrounding muscle fibers, characterized by IMAT expansion and the coordinated activation of adipogenic, extracellular matrix, inflammatory, and metabolic pathways. Spatial analyses showed that fibro-adipogenic progenitor (FAP) abundance does not predict adipocyte formation, supporting a model of localized and context-dependent lineage transitions. Cross-species comparison revealed partial conservation of human IMAT gene programs, validating the mouse model and highlighting species-specific features. Functional experiments in human primary myoblasts showed that EBF2 is sufficient to induce adipogenic reprogramming. Our findings establish IMAT as an active, spatially organized remodeling niche and identify lineage plasticity as a central mechanism driving its expansion in metabolic disease.