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.

Marseille Cancer Research Centre (CRCM), U1068 INSERM, UMR7258 CNRS, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, France · biorxiv

Paper

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 mTERT\'s 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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Research summary

The paper investigates the role of mTERT in obesity-induced metabolic disorders, focusing on mechanisms that involve adipose stem cell expansion and differentiation. This research touches on the underlying biological processes related to aging, such as cellular senescence and metabolic dysfunction, which are relevant to longevity. However, while the findings are solid and contribute to understanding the relationship between telomere biology and obesity, the impact is limited as it primarily addresses a specific metabolic disorder rather than providing broad insights into aging or lifespan extension.

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