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

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, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE261439 | GEO | 2026/03/12

REPOSITORIES: GEO

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Project description:Obesity due to overnutrition causes adipose tissue dysfunction, serving as a critical pathological step on the road to Type 2 diabetes (T2D) and other metabolic disorders. Here, we performed an unbiased investigation into the fundamental molecular mechanisms by which adipocytes transition to an unhealthy state during obesity. We fed NuTRAP (Nuclear tagging and Translating Ribosome Affinity Purification) mice crossed with Adipoq-Cre with chow or high fat diet (HFD) for 10 weeks and determined adipocyte-specific transcriptomic profiles by RNA-seq, active promoter and enhancer activities by H3K27ac ChIP-seq, and the PPARg cistrome by ChIP-seq. We also assessed the impact of the PPARg agonist rosiglitazone (Rosi) on gene expression and cellular state of adipocytes from HFD-fed mice. We used bioinformatic approaches to find transcriptional pathways and performed functional studies using shRNA-mediated loss-of-function approaches in 3T3-L1 adipocytes. Adipocytes from HFD-fed mice exhibited reduced expression of adipocyte markers and metabolic genes while showing enhanced expression of myofibroblast marker genes involved in cytoskeletal organization, accompanied by the formation of actin filament structures within the cell. PPARg binding was globally reduced in adipocytes after HFD feeding, and Rosi restored the molecular and cellular phenotypes of adipocytes associated with HFD feeding. SMAD binding motifs were over-represented in HFD-induced promoters and enhancers, while TGFb1 expression was elevated in adipose tissues after HFD feeding. TGFb1 treatment of mature 3T3-L1 adipocytes induced gene expression and cellular changes similar to those seen after HFD in vivo, and knockdown of Smad3 blunted the effects of TGFb1. Our data demonstrate that adipocytes fail to maintain cellular identity after HFD, acquiring characteristics of a myofibroblast-like cell type through reduced PPARg activity and elevated TGFb-SMAD signaling. This cellular identity crisis may serve as a fundamental mechanism that drives functional decline of adipose tissues during obesity.

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

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