Lipedema: A Disease Triggered by M2 Polarized Macrophages?

Background/Objectives: Lipedema is a progressive disease that results in the bilateral and symmetrical accumulation of subcutaneous fat in the legs and/or arms, affecting almost exclusively women. Methods: A comprehensive review of the peer-reviewed literature was conducted between November 2024 and February 2025. Results: The pathophysiology of lipedema is complex and, especially in the early stages, shows similarities to obesity, involving adipocytes, adipose tissue-resident macrophages, and endothelial cells. In lipedema, systemic levels and the adipocyte expression of the classical adipokines adiponectin and leptin appear normal, while it remains unclear if markers of inflammation and oxidative stress are increased. Macrophages in the adipose tissue of patients have an anti-inflammatory M2 phenotype and express high levels of the scavenger receptor CD163. These cells affect adipogenesis and seem to have a central role in adipose tissue accumulation. Increased lymphatic and blood vessel permeability are comorbidities of lipedema that occur in early disease states and may contribute to disease progression. Conclusions: This review summarizes our current understanding of the pathophysiology of lipedema with a focus on the role of stromal vascular localized M2 macrophages.