Chrysin stimulates UCP1-independent thermogenesis in 3T3-L1 adipocytes and mouse model

Emerging findings suggest that non-shivering thermogenesis in brown and beige adipocytes may effectively stimulate energy expenditure, thereby contributing to body weight reduction. Our previous report demonstrated that chrysin, a flavone found in honey and propolis, activates uncoupling protein 1 (UCP1)-dependent thermogenesis in brown fat and induces beige adipocytes. However, the effect of chrysin on UCP1-independent thermogenesis remains unexplored. In this study, we examined the effects of chrysin on UCP1-independent thermogenesis in the 3T3-L1 adipocytes and mouse model. This study showed that chrysin elevates the expression of calcium regulatory proteins, including sarcoendoplasmic reticulum Ca²⁺-ATPase, ryanodine receptor 2, voltage-dependent anion channel, mitochondrial calcium uniporter, and Ca²⁺/calmodulin-dependent protein kinase 2 in 3T3-L1 adipocytes as well as in inguinal and epididymal white adipose tissues of mice. Furthermore, our results also showed chrysin increased Ca²⁺ levels in 3T3-L1 adipocytes in a dose-dependent manner. In addition, our study showed chrysin upregulated creatine-mediated thermogenic markers (creatine kinase B and creatine kinase mitochondrial 2) in both in vitro and in vivo models. Mechanistically, we found that chrysin induces UCP1-independent thermogenesis by stimulating creatine- and calcium-mediated ATP-consuming futile cycle through the activation of the α1-adrenergic receptor. Combining the current and previous studies, it can be proposed that chrysin induces both UCP1-dependent and -independent thermogenesis in beige adipocytes, suggesting its possible use for effective intervention for obesity and metabolic disorders.