The Multiscale Heterogeneity of Adipose Tissue in Health and Disease

Adipose tissue has evolved from a passive lipid store to a dynamic, heterogeneous endocrine organ, whose dysfunction is closely linked to a cluster of chronic metabolic diseases. While early studies focused on overall adiposity, emerging evidence demonstrates that depot-specific adipose tissue traits outperform body mass index alone in predicting various disease risks. Adipose tissue heterogeneity refers to the inherent differences across distinct adipose depots, which manifest at anatomical, cellular, and molecular levels, alongside functional specialization. Moving beyond descriptive characterization, this review proposes a multiscale, functionally grounded framework that translates adipose heterogeneity into precision risk management and depot-targeted therapies. We provide a holistic update to cover previously underappreciated adipose depots (perivascular, epicardial, and bone marrow adipose tissues) and integrate recent single-cell sequencing discoveries of novel cell subsets in adipose tissues. We systematically summarize the core hallmarks of adipose heterogeneity and depot-specific roles in health and disease, while assessing the strength of evidence linking cellular subsets to functional outcomes. We also discuss how emerging technologies such as spatial transcriptomics, organoid technology, and artificial intelligence-driven imaging analysis resolve pathogenic niches and build translatable risk models. Finally, we propose a translational framework to overcome key bottlenecks from preclinical validation to clinical implementation, aiming to advance personalized management of diseases related to adipose tissue dysfunction.