A mitochondrial-stress adipocyte-macrophage circuit sustaining metaflammation in human type 2 diabetic adipose tissue

Type 2 diabetes mellitus (T2D) features chronic low-grade inflammation in white adipose tissue (WAT), where adipocytes and innate immune cells engage in immunometabolic crosstalk. Mitochondrial damage-associated molecular patterns (mtDAMPs) released from stressed adipocytes are thought to sustain metaflammation, but how they are handled by specific macrophage subsets in human T2D WAT is unclear. We hypothesized that in T2D subcutaneous white adipose tissue (scWAT), the mitochondrial stress-clearance circuit between adipocytes and macrophages becomes maladaptive. scWAT biopsies from 6 patients with T2D and 7 non-diabetic controls were profiled by single-nucleus RNA sequencing (snRNA-seq). We integrated transcriptomic data across donors, annotated adipocyte and immune cell states, and performed differential expression analysis along with pathway and immunometabolic module scoring. To map intercellular communication and mitochondrial waste handling, we applied metabolic flux inference (COMPASS), mitochondrial-derived vesicle (MDV) and phagocytosis gene signatures, ligand-receptor analysis (CellChat), and pseudotime trajectories of lipid-associated macrophages. Macrophages and adipocytes showed the strongest T2D-associated transcriptional and metabolic rewiring. We identified a stress-enriched adipocyte state (AD3) with upregulated mitophagy, vesicle and MDV trafficking, and inflammatory signaling, whose mitochondrial-stress module overlapped genes enriched in adipocyte-derived extracellular vesicles. Among lipid-associated macrophages, we resolved a LAM-ST1 subset with immunometabolic activation but downregulation of receptors and lysosomal programs for MDV uptake and degradation. Cell-cell communication and trajectory analyses indicated that AD3 engages LAM-ST1 through inflammatory and vesicular signaling and that LAM-ST1 occupies a terminal, clearance-incompetent branch along the LAM continuum, consistent with a maladaptive mitochondrial stress-clearance response. Our human snRNA-seq analysis delineates an adipocyte-macrophage immunometabolic circuit in which mitochondrial stress in AD3 adipocytes and defective MDV clearance by LAM-ST1 macrophages jointly sustain metaflammation in T2D scWAT. These findings highlight mitochondrial waste handling by tissue-resident macrophages as a potential checkpoint for restoring adipose immune homeostasis and reducing cardiometabolic risk.