Luteolin reduces fat storage in Caenorhabditis elegans by promoting the central serotonin pathway

Serotonin plays a critical role in regulating energy homeostasis and fat metabolism. Various dietary flavonoids, e.g. luteolin and quercetin, possess potential anti-obesity properties. However, it is unclear whether the flavonoids exert their anti-obesity actions via central serotonin signaling. Here, employing a classic animal model C. elegans, we assessed the effects of six dietary flavonoids (flavones apigenin, chrysin, and luteolin and flavonols kaempferol, myricetin, and quercetin) on fat accumulation. The dose-dependent study revealed the substantial inhibitory actions of the six flavonoids on C. elegans fat accumulation and the strongest inhibitory activity of luteolin among the tested flavonoids. Meanwhile, flavonoid treatments did not have an obvious influence on worm growth, fecundity and feeding. Furthermore, the mutation of tph-1, which encodes the conserved rate-limiting enzyme of serotonin synthesis, fully abolished luteolin-induced fat loss but did not affect fat reduction by the other five flavonoids. In wild-type N2 worms, luteolin treatment not only elevated the expression of tph-1, but also enhanced the mRNA levels of mod-1 and ser-6, which are two serotonin-related receptors and play specific roles in serotonin-mediated fat reduction. The mutation of either mod-1 or ser-6 also fully abolished luteolin-induced fat loss. Finally, we found that luteolin treatment elevated serotonin synthesis in ADF neurons to promote lipolysis and fatty acid β-oxidation in C. elegans. Together, the results indicated that luteolin reduced C. elegans fat storage by promoting central serotonin signaling, suggesting new insights into elucidating the mechanism underlying fat regulation by luteolin.