Lipedema as a disorder of adipose tissue heterogeneity: insights from single-cell and spatial transcriptomics.

Lipedema is a chronic adipose tissue disorder characterised by disproportionate accumulation of subcutaneous fat within specific anatomical depots, most commonly the lower extremities, with relative sparing of the trunk. Despite increasing clinical recognition, the mechanisms underlying the selective vulnerability of particular adipose depots and the progressive tissue remodelling observed in lipedema remain poorly understood. Emerging evidence suggests that lipedema is associated with complex alterations in adipocyte biology, adipose stem and progenitor cell (ASPC) function, immune signalling, vascular integrity, extracellular matrix remodelling, and lymphatic homeostasis, indicating that the disease extends beyond simple fat accumulation. Recent advances in adipose tissue biology have demonstrated that adipose depots are not functionally uniform structures, but rather anatomically distinct cellular ecosystems with unique developmental origins, transcriptional programs, stromal composition, immune niches, and metabolic properties. These depot-specific characteristics may provide an important framework for understanding the regional distribution and progression of lipedema. However, while substantial progress has been made in defining differences between visceral and subcutaneous adipose tissue, heterogeneity between individual subcutaneous depots remains comparatively underexplored despite its likely relevance to disorders of regional adipose expansion. The emergence of single-cell and spatial transcriptomic technologies has transformed the study of adipose tissue by enabling high-resolution mapping of adipocytes, stromal populations, vascular cells, and immune microenvironments within healthy and diseased tissue. These approaches offer an unprecedented opportunity to investigate depot-specific cellular states, intercellular signalling networks, and spatial tissue architecture in lipedema. In this review, we synthesise current evidence regarding tissue remodelling and adipose depot heterogeneity in lipedema and examine how single-cell and spatial omics approaches may advance mechanistic understanding of disease pathophysiology. We further discuss current technical and conceptual limitations within the field and highlight future directions for developing integrated adipose tissue atlases capable of identifying disease-driving cellular programs and therapeutic targets in lipedema.