Osteoprotegerin-Enabled Immune Evasion of Pathological Adipose Stromal Cells Drives Metabolic Dysfunction in Obesity.

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Diet-induced obesity (DIO) promotes the accumulation of stromal cells with senescent characteristics in the adipose tissue (AT). Selectively clearing these cells-either through chemical senolytics or activation of invariant natural killer T (iNKT) cells-improves glucose homeostasis in obese mice, however the identity of the responsible stromal population remains unknown. Here, we use transcriptional profiling of AT stromal cells coupled with C12FDG-based enrichment of senescent populations in mice with DIO and healthy controls to identify a distinct subset of adipose progenitor cells (APCs) with robust senescence signatures that accumulate in DIO across multiple AT depots. We show that these cells, which we term senescent APCs (sAPCs), are not merely passive markers of metabolic stress but are instead active stromal organizers, accumulating in parallel with the emergence of lipid-associated macrophages (LAMs) and the diminution of multipotent mesenchymal progenitors. sAPCs promoted CCR2-dependent macrophage chemotaxis, directly linking stromal senescence to chemokine-mediated remodeling of the AT immune niche. Comparative transcriptional analysis revealed a remarkable similarity between sAPCs and inflammatory cancer-associated fibroblasts (iCAFs), including the strong induction of periostin (POSTN) and the production of osteoprotegerin (OPG), a decoy receptor for RANKL and TRAI

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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