Macrophage activation of the TREM2-DAP12-SYK pathway shapes the adipose tissue microenvironment in obesity and unveils the therapeutic potential of natural compounds egcg and SMRR.

Obesity is a major global health burden, with current therapies limited by metabolic adaptation and adverse effects. Although transcriptomic studies reveal widespread gene alterations in obesity, key drivers and their cell-specific origins in adipose tissue remain unclear. Defining these regulators is critical for understanding immune-metabolic imbalance and developing targeted interventions. We integrated bulk transcriptomics (n=434) with single-cell RNA-seq (194,608 cells from 24 adipose samples) to identify BMI-associated gene modules and macrophage regulatory programs. Cell-specific networks, subtype-specific gene regulatory networks, pseudotime trajectories, and cell-cell communication analyses delineated macrophage heterogeneity. Molecular docking assessed interactions between candidate drugs and the TREM2-DAP12-SYK pathway, and in vivo studies evaluated the therapeutic potential of EGCG and SMRR in high-fat diet mice. Our analyses revealed significant molecular and microenvironmental differences between healthy and obese adipose tissue. Eight BMI-associated genes-SYK, CD86, CSF1R, HCK, TYROBP, LAPTM5, ITGB2, and ACTB-were predominantly expressed in macrophages. Single-cell profiling identified macrophage subtypes (C4, C6, C10) with distinct regulatory roles in adipocyte communication. Dysfunction of the TREM2-DAP12-SYK axis underpinned obesity-associated macrophage states, while EGCG and SMRR reactivated this pathway, mitigating obesity and metabolic dysfunction in vivo. These findings define a macrophage-centered regulatory network driving obesity progression and highlight actionable therapeutic targets.