Apigenin Mitigates Circadian Metabolic Dysfunction via Microbiota-Driven Suppression of HDAC3-Mediated Lipid Uptake
Prolonged exposure to artificial environmental light disrupts circadian rhythms and serves as a crucial driver of metabolic dysfunction. Effective clinical management necessitates a dual-action approach capable of concurrently resynchronizing biological rhythms and reversing metabolic deficits. This study evaluates the dietary flavonoid apigenin as a novel chronotherapeutic strategy to address this multifaceted pathology. Mice were subjected to constant light and high-fat diet (HFD) to simulate environmental circadian disruption. The therapeutic efficacy of apigenin was assessed through molecular clock profiling, melatonin quantification, and 16S rDNA sequencing. Fecal microbiota transplantation (FMT) was utilized to determine the transmissibility of metabolic benefits. Mechanistic investigations included molecular dynamics (MD) simulations and gene expression analyses to characterize the interaction between apigenin and the histone deacetylase 3 (HDAC3) signaling pathway. Apigenin successfully resynchronized the core molecular clockwork and restored systemic melatonin levels while significantly mitigating metabolic dysfunction. These improvements were accompanied by a robust remodeling of the gut microbiota with enrichment of beneficial genera including Blautia and Akkermansia. FMT confirmed that the apigenin-modulated microbiome was sufficient to improve metabolic health and reinforce intestinal barrier integrity in recipient mice. Mechanistically, apigenin suppressed intestinal lipid absorption by inhibiting histone deacetylase 3 through a dual regulatory mechanism. This involved the microbiota-dependent transcriptional repression of ileal Hdac3, which subsequently downregulated the lipid transporter Cd36, as well as direct binding to the catalytic pocket of the HDAC3 protein. These findings identify a novel microbiota-HDAC3 signaling axis that governs intestinal lipid flux. By simultaneously targeting circadian and metabolic pathways, apigenin provides a promising chronotherapeutic strategy for the management of metabolic disorders driven by environmental and occupational circadian disruption.