Fang Liu, Cao-an Hong, Shiqin Gong, Zhongyu Fan, Xin Xiao, Yi Xiao
Targeted regulation of lipid homeostasis through pharmacological interventions is good strategy to combat obesity and prolong lifespan across various organisms. Luteolin derived from edible plants exhibits widespread pharmacological activity. Here, we found that low-lipid phenotype induced by luteolin was transmitted to multigenerational progeny. Intriguingly, we found that DAF-16/FOXO and NHR-49/PPAR-α, along with β-oxidation genes and Δ9 desaturases, were essential for transgenerational fat regulation. Furthermore, H3K4me3 marks fat metabolism genes and enhances their transcription during multigenerational low-lipid inheritance. Importantly, we showed that luteolin activated the nuclear receptor NHR-49/PPAR-α in turn up-regulated transcription of the Δ9 desaturases, leading to increased MUFAs content, which was required for healthspan extension. Furthermore, by screening the classical pathways, we found that luteolin also promoted the healthspan via DAF-16. Our research has shown that luteolin reduces fat and extends lifespan through the same mechanism and luteolin is a potential molecule for weight loss and anti-aging.