TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation

Braud, L.; Bernabe, M.; Vernerey, J.; Miranda, A. M. A.; Dominguez, A.; Churikov, D.; Richaud, M.; McAllan, L.; Lachaud, C.; Gil, J.; Scott, W.; Geli, V.

doi:10.1101/2025.01.06.631346

bioRxiv · 10.1101/2025.01.06.631346

TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation

Braud, L.·Bernabe, M.·Vernerey, J.·Miranda, A. M. A.·Dominguez, A.·Churikov, D.·Richaud, M.·McAllan, L.·Lachaud, C.·Gil, J.·Scott, W.·Geli, V.

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Abstract

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert (p21+/Tert) from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders. Conditional expression of mTERT reduces metabolic disorders 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 show that ASPC expansion and differentiation are promoted in p21+/Tert obese mice, thereby reducing metabolic disorders. We further report that mTERT remodels the landscape of macrophages in AT of obese mice. Strikingly, inactivation of mTERT catalytic activity in p21+/Tert (p21+/TertCi) mice suppresses the promotion of adipocyte formation, but neither affects attenuation of senescence nor macrophage remodeling. These results highlight mTERTs canonical and non-canonical functions in reducing obesity-associated metabolic disorders. Conditional expression of TERT thus appears as a potential therapeutic option for obesity.

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Braud, L., Bernabe, M., Vernerey, J., Miranda, A. M. A., Dominguez, A., Churikov, D., Richaud, M., McAllan, L., Lachaud, C., Gil, J., Scott, W., Geli, V.. 2025-01-06. TERT prevents obesity-induced metabolic disorders by promoting adipose stem cell expansion and differentiation. https://doi.org/10.1101/2025.01.06.631346

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