TERT expression attenuates metabolic disorders in obese mice by promoting adipocyte formation and remodeling macrophage landscape [RNA-Seq]

Obesity is linked to limited adipose tissue (AT) remodeling capacity, leading to hypertrophic adipocytes, senescence, and inflammation. We used a mouse model expressing mTert, or its catalytically inactive form mTertCi, from the Cdkn1a locus to investigate the role of mTERT in obesity-induced metabolic disorders in mice on a high-fat-diet (HFD). We found that mTERT expression attenuates p21 expression, telomere attrition, senescence, and inflammation in the AT of HFD-induced obese mice, thereby reducing associated metabolic disorders. In vivo and in vitro data reveal that mTERT promotes differentiation of adipose stem and progenitor cells into adipocytes in obese mice. Strikingly, single nucleus RNA-seq data show that both mTERT and mTERTCi remodels the landscape of macrophages in AT of obese mice thereby reducing the immune response. These results emphasize involvement of the canonical and non-canonical mTERT functions in ameliorating metabolic disorders and suggest conditional TERT expression as a potential therapeutic option for obesity.