Metabolism. 2026 Aug 05. pii: S0026-0495(26)00242-8. [Epub ahead of print]
156729
Yumeng Wang,
Jiajie Li,
Weijiong He,
Furong Zhao,
Yunzi Kang,
Yewei Cui,
Hongxiang Zeng,
Ting Zeng,
Rui Cheng,
Shujin Wang,
Linqiang Zhang,
Rui Wang,
Xueya Zhao,
Liuling Xiao,
Xi Li.
Beiging of white adipose tissue (WAT) is a promising strategy to enhance energy expenditure and combat obesity, a growing global health burden. Here, we identify a non-canonical role of caspase-1, a cysteine protease, in regulating adipocyte thermogenesis. Caspase-1 expression in adipocytes of inguinal WAT is downregulated upon cold exposure but elevated in obesity. Adipocyte-specific caspase-1 deficiency promotes WAT beiging, increases whole-body energy expenditure, and ameliorates high-fat diet-induced obesity and metabolic dysfunction. Mechanistically, cAMP signaling suppresses Casp1 transcription via C/EBPβ. Proteomic and functional analyses reveal that caspase-1 interacts with and modulates the protein levels of COX7A2L, a subunit of mitochondrial complex IV. Loss of Casp1 stabilizes COX7A2L, thereby enhancing mitochondrial respiration. Moreover, CASP1 expression in human WAT significantly increases with obesity and metabolic dysfunction. Accordingly, we developed a sustained-release delivery system for the caspase-1 inhibitor Ac-YVAD-CHO, which effectively protects against diet-induced obesity and improves glucose tolerance in mice. These findings reveal a previously unrecognized inflammation-independent role of adipocyte-intrinsic caspase-1 in adipose beiging and highlight caspase-1 as a potential therapeutic target for obesity.
Keywords: Adipocyte; COX7A2L; Caspase-1; Metabolic homeostasis; White fat beiging