Adipose Cirbp protects against diet-induced obesity by regulating Vav3 to promote brown fat thermogenesis

Brown adipose tissue (BAT) thermogenesis has emerged as a critical therapeutic target for obesity. However, the precise regulatory mechanisms remain incompletely elucidated. Cold-inducible RNA binding protein (CIRBP) is a stress-responsive molecule involved in the regulation of energy metabolism in various tissues; however, its function in adipose tissue remains unclear. This study aimed to characterize the function and molecular mechanism through which Cirbp regulates BAT thermogenesis. A mouse model with adipose tissue-specific Cirbp knockout ( Cirbp Adq−/− ) was constructed, and obesity and cold exposure models were developed using high-fat diet (HFD) feeding and cold stimulation, respectively. Various methods, including indirect calorimetry, histological analysis, RT‒qPCR, Western blotting, RNA sequencing (RNA-seq), RNA immunoprecipitation combined with sequencing (RIP-seq), and molecular docking, were employed to evaluate how Cirbp affects BAT thermogenesis and systemic energy metabolism. Cirbp expression in BAT was dynamically modulated by cold exposure, with significant upregulation detected upon prolonged stimulation in a tissue-specific manner. Cirbp deficiency in adipose tissue ( Cirbp Adq−/− mice) markedly reduced both basal and cold-induced systemic energy expenditure, compromised cold tolerance, suppressed BAT thermogenesis, and impaired mitochondrial function. After HFD feeding, C irbp Adq−/− mice displayed significant exacerbation of obesity and metabolic dysfunction, accompanied by a further reduction in BAT thermogenic capacity. In vitro experiments confirmed that Cirbp positively regulates brown adipocyte differentiation and thermogenesis. Mechanistically, integrated RIP-seq and transcriptomic analyses revealed that Vav3 is a direct downstream target of CIRBP in BAT. CIRBP specifically interacts with the 3’ untranslated region (3’UTR) of Vav3 mRNA, thereby increasing the stability of this transcript. Moreover, molecular docking and MD simulations confirmed that CIRBP forms a conformationally stable protein complex with VAV3. Functional rescue experiments demonstrated the essential role of Vav3 in Cirbp -mediated thermogenesis, as Vav3 silencing completely abolished the thermogenic effects induced by Cirbp overexpression. This study identifies Cirbp as a critical positive regulator of BAT thermogenesis, which acts by specifically modulating Vav3 expression. Targeting the Cirbp–Vav3 axis in BAT might be a novel strategy for treating obesity.