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CTAGE5 is essential for adipogenesis and adipose tissue development

ABSTRACT: White adipocytes serve as primary energy reservoirs and their malfunction is linked to different metabolic disorders, yet the mechanisms underlying cellular specialization, a critical step during adipogenesis remain unknown. Here, we reveal the indispensable role of cutaneous T cell lymphoma-associated antigen 5 (cTAGE5) in adipocyte differentiation and maturation. Conditional deletion of cTAGE5 in adipocyte precursor cells (APCs), rather than mature adipocytes, results in progressive loss of white adipose tissue and death of mice. Mechanistically, cTAGE5 deficiency in APCs disturbs pro-insulin receptor (IR) processing and impairs insulin signaling, companied by significant down-regulation of actin cytoskeleton related genes and defect in cytoskeleton remodeling, alongside enhanced expression of proteins associated with lipid catabolic process and lipolysis in white adipose tissue. Importantly, inhibitors targeting actin polymerization and lipolysis effectively restore adipocyte differentiation capacity in cTAGE5-deficient APCs. Collectively, our findings demonstrate that cTAGE5 plays pivotal roles in adipogenesis and adipose tissue development.

ORGANISM(S): Mus Musculus

SUBMITTER: Wenyan He

PROVIDER: PXD059525 | iProX | Tue Jan 07 00:00:00 GMT 2025

REPOSITORIES: iProX

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cTAGE5 is essential for adipogenesis and adipose tissue development.

Fan Junwan J Ma Tiantian T Ren Xiaoping X Chang Zhilin Z Zhang Dan D Wang Yi Y Cheng Shiyao S Qi Xin X Liu Kehui K Wang Yan Y Wang Yaqing Y Xu Zhiheng Z He Wenyan W

Nature communications 20250701 1

White adipocytes serve as primary energy reservoirs and their malfunction is linked to different metabolic disorders, yet the mechanisms underlying cellular specialization, a critical step during adipogenesis remain unknown. Here, we reveal the indispensable role of cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5) in adipocyte differentiation and maturation. Conditional deletion of cTAGE5 in adipocyte precursor cells (APCs), rather than mature adipocytes, results in progressive loss of wh ...[more]

PMID: 40593547

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Project description:Aims: Adipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we investigate the role of Heart and neural crest derivatives-expressed protein 2 (HAND2) in adipogenesis. Methods: Human white adipose tissue (WAT) were collected in a cross-sectional study of 318 individuals. In vitro, for mechanistic experiments we used primary adipocytes from human and mice as well as human multipotent adipose derived stem (hMADS) cells. Gene silencing was performed using siRNA or genetic inactivation in primary adipocytes from LoxP mouse models with Cre-encoding mRNA. Adipogenesis efficiency was measured by OilRedO staining, qPCR and microarray. A combinatorial RNASeq approach was used to identify gene clusters regulated by HAND2. In vivo, we created a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter (HAND2AdipoqCRE). Results: We found that HAND2 is an obesity-linked white adipocyte transcription factor regulated by glucocorticoids that was required but insufficient for adipocyte differentiation in vitro. In a large cohort of humans with obesity, WAT HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes compared to brown, induced early in differentiation and responded to DEX, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in hMADS or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by GCs via GR in vitro and in vivo. Furthermore, we identified gene clusters indirectly regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. Conclusion: In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

Project description:Abstract Background In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The individual ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to the development of inflammation and detrimental metabolic consequences. However, the molecular mechanisms underlying this fine-tuned regulation are far from being understood. Methods We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low responders (LowR HFD), showed a low susceptibility to the onset of adipose tissue inflammation, as opposed to their HFD counterpart. We identified the discriminants between LowR HFD and HFD vWAT samples and explored their function in Adipose Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes. Results We quantified 6051 proteins. Among the candidates that most differentiate LowR HFD from HFD vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in LowR HFD, as compared to HFD. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was totally unknown, was another top-scored hit. SMYD3 expression was significantly higher in LowR HFD vWAT, as confirmed by western blot analysis. In vitro, we found that SMYD3 mRNA and protein levels decrease rapidly along the differentiation process of AD-hMSCs. Moreover, SMYD3 knock-down at the beginning of adipocyte differentiation resulted in reduced cell proliferation and, at longer term, reduced lipid accumulation in adipocytes. Conclusions Our study describes for the first time the role of SMYD3 as a regulator of adipocyte proliferation during the early steps of adipogenesis.

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CTAGE5 is essential for adipogenesis and adipose tissue development

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cTAGE5 is essential for adipogenesis and adipose tissue development.

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