Adipocyte caspase-1 deficiency promotes white fat beiging via COX7A2L-dependent mitochondrial respiration.

Abstract

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.