TERT expression attenuates metabolic disorders in obese mice by promoting adipose stem and progenitor cell expansion and differentiation.

Background and aims: Adipose tissue (AT) senescence, induced by obesity or aging, leads to a reduced capacity for tissue remodeling and a chronic pro-inflammatory state, which leads to the onset of metabolic pathologies. Cellular senescence is triggered by various stresses, in particular excessive shortening of telomeres, which activates the p21 pathway and leads to the arrest of the cell cycle. We used the mouse model p21^+/Tert expressing TERT from the Cdkn1a locus to investigate whether counteracting telomere shortening by telomerase (TERT) specifically in pre-senescent cells could improve obesity-induced metabolic disorders.

Results: Our study demonstrates that conditional expression of TERT reduces insulin-resistance and glucose intolerance associated with obesity. In AT, this is accompanied by a decrease in the number of senescent p21-positive cells, very short telomeres, and oxidative DNA damage. Single nucleus RNA-seq data reveal TERT expression attenuates senescence induced by HFD in particular in adipose stem and progenitor cells (ASPC). We demonstrate that ASPC expansion and differentiation are promoted in p21^+/Tert obese mice, thereby improving AT plasticity. Furthermore, we show that TERT expression enhances mitochondrial function and alleviates oxidative stress in ASPC. This process contributes to the AT hyperplasia with increased number of adipocytes which has been shown to have a protective effect against obesity-associated metabolic disorders.

Conclusions: These results underscore TERT's role in mitigating obesity-related metabolic dysfunction. Conditional TERT expression may therefore represent as a promising therapeutic strategy for obesity-associated metabolic disorders.