Tissue-specific thyroid hormone signaling participates in subcutaneous adipose tissue alteration in the aging process

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Functional changes in subcutaneous adipose tissue (SAT) occur earlier in the aging process and play an important role in the occurrence and development of age-related metabolic diseases. The mechanism of this phenomenon is still unclear, and the change in adipose tissue with age is poorly understood. The combination of gene expression (RNA-seq) and chromatin accessibility (ATAC-seq) was established in SAT from human subjects to investigate the major alterations and discover the associated key factors in the aging process. In the present study, RNA-seq revealed that 331 genes were upregulated and 349 genes were downregulated in SAT from elderly individuals. Oxygen consumption experiments and immunofluorescence staining also showed alterations in mitochondrial function in SAT of different ages. ATAC-seq identified the dynamics of chromatin accessibility of the SAT genome at different ages, which were enriched in thyroid hormone receptors and their co-transcription factor-binding sites. Combined analysis identified seven specific genes related to mitochondrial function, including NCF1, NLRP3, DUOX1, IFI30, P2RX1, P2RX6, and PRODH. In vitro experiments verified that the transcriptional expression of the seven genes was regulated by thyroid hormone. Thus, the present study demonstrated that in elderly individuals, the function, in addition to distribution, of SAT undergoes significant changes, primarily in mitochondria, which may be due to tissue-specific insensitivity to thyroid hormone signaling.

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