A transcriptionally distinct population of human adipocytes with end-of-trajectory signature (hEOS) emerges during obesity to drive maladaptive inflammation.

Maladaptive interactions between adipocytes and immune cells drive obesity-associated inflammation, yet pharmacological interventions targeting this mechanism remain scarce. Here, we identify a disease-emergent, spatially organized, and conserved immunometabolic module within the obese white adipose tissue (WAT) microenvironment, reflecting the coordinated crosstalk between adipocytes and macrophages. By integrating single-nucleus RNA sequencing, spatial transcriptomics, and bulk RNA-seq across 247,406 nuclei from 489 individuals, we identified a transcriptionally distinct population of adipocytes with high end-of-trajectory signature (hEOS). This population, characterized by impaired adipokine secretion and defective insulin signaling, re-emerges in obesity and contributes to pathogenic WAT remodeling. These hEOS cells preferentially colocalize with a conserved macrophage subset (Mac3) within discrete niches, forming a co-adapted spatial unit that contributes to maladaptive inflammation. Mechanistically, HIF1A activation in hEOS under hypoxic conditions is associated with increased expression of the extracellular matrix protein LAMA4, which contribute to niche remodeling and is spatially associated with Mac3 macrophages. Our data further suggest that LAMA4 signals through an ITGB1-mediated pathway to promote NF-κB activation in Mac3 cells. The overall activity of this axis correlates with BMI, HbA1c, and insulin resistance in humans. Importantly, pharmacological intervention with the IKKε/TBK1 inhibitor amlexanox improved metabolic dysfunction in vivo, and this was accompanied by reduced adipocyte Lama4 expression and suppressed pro-inflammatory macrophage activation, consistent with attenuation of the hEOS-Mac3 module. Together, these findings define hEOS adipocytes as a disease-emergent, pharmacologically responsive population that is implicated in maladaptive adipocyte-macrophage crosstalk and prioritize the LAMA4-integrin-NF-κB axis as a potential therapeutic target.