Decreased YB-1 expression denervates brown adipose tissue and contributes to age-related metabolic dysfunction.

Thermogenesis in brown adipose tissue (BAT) declines with aging, however, the underlying mechanism remains unclear. Here, we show that the expression of Y-box binding protein 1 (YB-1), a critical DNA/RNA binding protein, decreased in the BAT of aged mice due to the reduction of microbial metabolite butyrate. Genetic ablation of YB-1 in the BAT accelerated diet-induced obesity and BAT thermogenic dysfunction. In contrast, overexpression of YB-1 in the BAT of aged mice was sufficient to promote BAT thermogenesis, thus alleviating diet-induced obesity and insulin resistance. Interestingly, YB-1 had no direct effect on adipose UCP1 expression. Instead, YB-1 promoted axon guidance of BAT via regulating the expression of Slit2, thus potentiating sympathetic innervation and thermogenesis. Moreover, we have identified that a natural compound Sciadopitysin, which promotes YB-1 protein stability and nuclear translocation, alleviated BAT aging and metabolic disorders. Together, we reveal a novel fat-sympathetic nerve unit in regulating BAT senescence and provide a promising strategy against age-related metabolic disorders.