Obesity-induced pyroptotic adipocyte death leads to TREM2-dependent macrophage dysfunction and adipose tissue inflammation

Triggering receptor expressed on myeloid cells 2 (TREM2) is a key marker of lipid-associated macrophages (LAMs), but its role in adipose tissue homeostasis remains unclear due to conflicting results. This study aimed to investigate the role of TREM2 in adipose tissue inflammation and metabolic dysfunction during high-fat diet (HFD)-induced obesity. HFD feeding enhanced proteolytic cleavage of TREM2 in gonadal white adipose tissue (GWAT), driven by upregulation of the metalloproteinase ADAM10 and ADAM17. <i>In vitro</i> co-culture of RAW264.7 cells with pyroptotic, but not apoptotic, adipocytes increased stimulator of interferon genes (STING) activation, upregulated ADAM10/17 expression, and promoted TREM2 shedding. Pharmacological inhibition of ADAM10/17 by GM6001 reduced TREM2 cleavage and enhanced phagocytosis of dying pyroptotic adipocytes. <i>In vivo</i> GM6001 treatment attenuated HFD-induced weight gain, improved metabolic parameters, and shifted macrophage polarization toward anti-inflammatory TREM2+CD206+ subsets. These findings demonstrate that pyroptotic adipocyte death promotes pathological TREM2 shedding, contributing to macrophage dysfunction and adipose tissue inflammation.