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

Figures

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  Figure 1. Remodeling of the adipose-tissue microenvironment and macrophage accumulation during obesity. In lean adipose tissue, adipocytes are relatively small and macrophages are sparsely distributed. Obesity-associated adipocyte hypertrophy, hypoxia, and endoplasmic reticulum (ER) stress promote adipocyte dysfunction and death, with the release of lipids and damage-associated molecular patterns (DAMPs). C–C motif chemokine ligand 2 (CCL2)–C-C chemokine receptor type 2 (CCR2) signaling recruits circulating monocytes, which contribute to adipose-tissue macrophage (ATM) accumulation and crown-like structure (CLS) formation around dead or dying adipocytes. Dashed red arrows denote associations of CLS-associated macrophage accumulation with TNF-α, IL-6, IL-1β, and insulin resistance; they do not imply that these outcomes are specific to molecularly defined LAMs.

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  Figure 2. Candidate origin, LAM-associated clearance features, and context-dependent roles of adipose LAMs. The dashed monocyte–pre-LAM-like–LAM sequence denotes an inferred state-transition model rather than a fate-mapped lineage. Solid relationships indicate lipid-handling and lysosomal features supported in adipose-LAM studies but do not establish enhanced metabolic flux. Efferocytosis is shown as a supportive relationship because molecularly and spatially defined adipose LAMs were not uniformly isolated in the relevant functional studies. The potential lipid-buffering and inflammation/remodeling outcomes represent context-dependent alternatives rather than a confirmed temporal progression. Solid lines indicate supported adipose-LAM features; dashed lines indicate supportive, inferred, or proposed relationships.

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  Figure 3. Evidence-graded framework for immunometabolic programs associated with adipose LAMs. Solid relationships summarize molecular or spatial features supported in adipose-LAM studies. TREM2/CD9 expression, LPL/LIPA enrichment, lipid-handling and lysosomal programs, and CLS localization are presented as parallel associated features rather than as a causal sequence. Dashed relationships denote supportive evidence from total adipose-tissue macrophages or indirect evidence from other macrophage systems. Glycolysis/HIF-1α and OXPHOS/AMPK–mTOR are therefore shown as supportive ATM frameworks, whereas the TREM2–DAP12–SYK–PI3K–AKT–mTOR and NF-κB/JNK/NLRP3 modules are not presented as a unified LAM-specific cascade.