Non-canonical TERT function mitigates adipose tissue inflammation in obesity by modulating stem cell-macrophage communication and macrophage states

Background and aims Obesity drives adipose tissue (AT) expansion and chronic inflammation, leading to metabolic dysfunction through adipocyte hypertrophy, impaired ASPC differentiation, immune infiltration, and fibrosis. Stromal vascular remodeling prominently features expansion of Gdf15- and Trem2-expressing lipid-associated macrophages (LAMs), which respond to adipocyte stress and act as lipid scavengers to buffer excess lipids released by adipocytes. Here, we examined macrophage reprogramming in p21 +/Tert and p21 +/TertCi mice, which express active TERT or its catalytically inactive TERT Ci mutant from the endogenous Cdkn1a promoter. Results Following HFD exposure, conditional expression of TERT or TERT Ci resulted in a pronounced downregulation of p21 in macrophage subsets, accompanied by a reduction in AT inflammation. Notably, TERT and TERT Ci expression reshaped the adipose-tissue macrophage (ATM) landscape depleting Trem2+ and Gdf15+ LAMs while preserving resident macrophages. This shift was accompanied by marked suppression of the Trem2 transcriptional program and down-regulation of PPAR-γ and NR1H3 in LAMs and by impaired ASPC-LAM signaling pathways that normally drive LAM recruitment and activation. Proteomic profiling further showed that p21 +/Tert ASPCs secreted markedly higher levels of proteins associated with non-conventional secretion, while extracellular matrix–associated factors and cytokines/chemokines including key mediators of ASPC–LAM communication such as Ccl2, C3, and Csf1 were substantially reduced. However, only p21 +/Tert mice, and not p21 +/TertCi mice, exhibited significant metabolic improvements, indicating that macrophage remodeling alone is insufficient to restore systemic metabolic function. Consistent with this, enhanced ASPC expansion and differentiation, supporting improved adipose-tissue remodeling, was observed exclusively in p21 +/Tert obese mice. Conclusions TERT remodels adipose tissue immunity independently of its enzymatic activity, and TERT-driven reprogramming of the ASPC secretome may emerge as a promising strategy to combat obesity-related metabolic dysfunction. Highlights Conditional expression of TERT or catalytically inactive TERT Ci results in the depletion Trem2+ and Gdf15+ LAMs while preserving resident macrophages TERT and TERT Ci expression impairs ASPC-adipocyte/LAM communication pathways that normally drive LAM recruitment and activation. In vitro, TERT conditional expression in ASPCs promotes non-conventional protein secretion and reduces the secretion of key mediators of ASPC–LAM communication Only p21 +/Tert mice, and not p21 +/TertCi mice, exhibited enhanced ASPC expansion, improved adipose-tissue remodeling, and systemic metabolic benefits, demonstrating that macrophage remodeling alone is insufficient to restore metabolic function.