Asprosin drives obesity by inducing ferroptosis and dysfunction of brown adipocytes mediated by Notch3/RBP-Jκ/VDAC3 axis

The pathogenesis of obesity is complex, and dysfunction of brown adipose tissue (BAT) is increasingly recognized as a key contributor. The role and underlying mechanisms of adipokine asprosin (ASP) in obesity remain to be fully elucidated. This study aimed to investigate the specific effect of adipose-derived ASP on systemic metabolism and BAT function and to elucidate the underlying molecular mechanisms involving ferroptosis. We generated adipose tissue–specific ASP deficiency (ASP −/− ) mice and evaluated gluco-lipid metabolism, BAT thermogenesis, ferroptotic markers, and downstream signaling components through biochemical assays, histology, and molecular profiling. ASP −/− markedly improves systemic gluco-lipid metabolism in mice. This beneficial effect is associated with enhanced BAT function and a significant suppression of ferroptosis in brown adipocytes. Mechanistically, ASP directly binds to Notch3, which impedes the proteolytic cleavage and subsequent nuclear translocation of Notch3 intracellular domain (NICD). This interaction inhibits the formation of the NICD/RBP-Jκ transcriptional complex, ultimately leading to reduced transcription of the downstream target gene voltage-dependent anion channel 3 (VDAC3). Our findings demonstrate that ASP provokes BAT dysfunction and obesity by inducing ferroptosis through inhibiting Notch3/RBP-Jκ/VDAC3 signaling. This study reveals a novel mechanistic insight into obesity pathogenesis and suggests that targeting ASP could be a promising therapeutic strategy for metabolic disorders. Not applicable.