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<p>Age-related obesity is a growing public health concern linked to various metabolic disorders, yet its underlying mechanisms remain incompletely understood. Here we report that <i>S</i>-nitrosoglutathione reductase (GSNOR), a pivotal denitrosation enzyme, increases in adipose tissue of both male mice and humans from middle-age. GSNOR knockout protects against age-related weight gain and enhances metabolism, whereas adipose-specific GSNOR knock-in mice promotes obesity and metabolic decline. Further investigation reveals that aged GSNOR KO mice maintain higher mitochondrial content and more beige adipocytes, whereas adipose-specific GSNOR overexpression promotes adipose tissue whitening. Mechanistically, GSNOR denitrosates Beclin-1 at cysteine 351 and mutation of this site (Beclin-1C351A) increases autophagy by enhancing Beclin-1 and ATG14 interaction, thereby accelerating beige-to-white adipocyte conversion. Together, our findings reveal that GSNOR regulates adipose tissue remodeling during aging through Beclin-1 <i>S</i>-nitrosation, pointing to a potential therapeutic target for age-related obesity.</p>

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S-nitrosoglutathione reductase GSNOR drives age-related obesity by promoting adipose tissue whitening through de-nitrosation of Beclin-1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月23日

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  • Xinhua Qiao,
  • Ting Xie,
  • Yuying Zhang,
  • Chuanxin Sun,
  • Xuanhao Wu,
  • Yuzhe Chen,
  • Qin Yao,
  • Haoyang Shi,
  • Shilong Li,
  • Hongyu Zhao,
  • Tiepeng Wang,
  • Jiao Meng,
  • Li Zhou,
  • Mutian Niu,
  • Yangxi Hu,
  • Hansong Liu,
  • Chang Chen

摘要

Age-related obesity is a growing public health concern linked to various metabolic disorders, yet its underlying mechanisms remain incompletely understood. Here we report that S-nitrosoglutathione reductase (GSNOR), a pivotal denitrosation enzyme, increases in adipose tissue of both male mice and humans from middle-age. GSNOR knockout protects against age-related weight gain and enhances metabolism, whereas adipose-specific GSNOR knock-in mice promotes obesity and metabolic decline. Further investigation reveals that aged GSNOR KO mice maintain higher mitochondrial content and more beige adipocytes, whereas adipose-specific GSNOR overexpression promotes adipose tissue whitening. Mechanistically, GSNOR denitrosates Beclin-1 at cysteine 351 and mutation of this site (Beclin-1C351A) increases autophagy by enhancing Beclin-1 and ATG14 interaction, thereby accelerating beige-to-white adipocyte conversion. Together, our findings reveal that GSNOR regulates adipose tissue remodeling during aging through Beclin-1 S-nitrosation, pointing to a potential therapeutic target for age-related obesity.