5-Hydroxytryptamine mediated 5-HTR4-ILP axis orchestrates glucose utilization and glycogen storage in the Pacific oyster (Crassostrea gigas)

Glycogen originating from animal-derived foods is increasingly perceived as a high-quality nutrient and an unignorable component of the diet. 5-hydroxytryptamine (5-HT) has been identified to regulate glycogen-targeted nutrient traits based on multi-omics analysis, yet its molecular regulatory mechanisms remain unclear. In this study, we reveal that the 5-HT mediated 5-HTR4-ILP regulatory axis orchestrates glucose utilization and glycogen synthesis in the Pacific oyster (Crassostrea gigas). We find that 5-HT system in oysters is glucose-sensitive and its activation directs the metabolic fate of glucose toward glycogen accumulation. Phylogenetic analysis combined with glucose treatments identifies 5-HTR4 as the core receptor that triggers a series of downstream signaling cascades, including canonical cAMP/PKA pathway, along with the noncanonical MAPK, mTOR and AMPK pathways. These signals are integrated by nuclear CREM transcription factor, which binds to the CRE element on the promoter of insulin-like peptides (ILPs), thereby initiating gene transcription followed by facilitating the uptake and conversion of glucose into glycogen. This study establishes a 5-HT mediated molecular regulatory network governing metabolic processes, offering novel targets for the enhancement of glycogen quality traits in oysters and other food animals.