Lipid-Associated Macrophages in Obesity: Immunometabolic Programs and Emerging Therapeutic Implications—A Narrative Review

Abstract

Abstract Obesity-associated adipose tissue inflammation is accompanied by the expansion of macrophage populations enriched in lipid-handling, lysosomal, and phagocytic programs, commonly referred to as lipid-associated macrophages (LAMs). Single-cell and spatial studies support their accumulation in crown-like structures and other lipid-rich adipose tissue niches, with partially conserved LAM-like populations also identified in humans. However, direct functional evidence, particularly in human adipose tissue, remains limited. Experimental studies suggest that LAMs may participate in lipid sequestration, efferocytosis, lysosomal processing, and inflammatory regulation, although their net effects appear to vary according to species, adipose depot, metabolic stage, and experimental model. The proposed transition from an adaptive lipid-buffering state to a chronically inflammatory state should therefore be regarded as a context-dependent working model rather than an established temporal sequence. This narrative review critically examines how LAMs are defined, distinguishes direct adipose LAM evidence from findings extrapolated from broader macrophage systems, and integrates lipid metabolism, bioenergetic remodeling, inflammatory signaling, and therapeutic evidence within an explicit evidence hierarchy. Current interventions act mainly through broader macrophage, adipose tissue, or systemic metabolic pathways, and no selective LAM-targeted therapy is currently available. Further translation will require robust human LAM definitions, longitudinal functional studies, reliable biomarkers, and strategies that modify detrimental LAM-associated functions without disrupting beneficial macrophage activities.