Study on the signaling pathways involved in the anti-hyperglycemic effect of raspberry ketone on zebrafish using integrative transcriptome and metabolome analyses

Hyperglycemia leads to increased oxidative stress in mitochondria, an abnormal activation of intracellular inflammatory signals, and mediate multiple dysfunctions. Raspberry ketone (RK) is an aromatic phenolic compound found in many plants and could contribute to weight loss, restore impaired glucose tolerance, and has antioxidant properties. In our investigation, RK could greatly prevent islet, brain and other tissue damage caused by hyperglycemia in a zebrafish model with streptozotocin (STZ)-induced hyperglycemia. Body weight, insulin level, and food intake indexes were also restored by RK. Using transcriptome profiling, we found that RK administration could significantly attenuate STZ-induced insulin synthesis and pancreatic secretion as well as alter protein and carbohydrate metabolism. Metabolomics analysis results showed that RK could also prevent STZ-induced metabolic disorders, such as adenosine and sphingolipid metabolism. Integrative analysis of metabolome and transcriptome data and qRT-PCR validation of key metabolic regulatory genes (glut1, glut2, ctrb1, ccka, gck, pklr) confirmed that the purine pathway was the most enriched metabolic pathway, in which both metabolite accumulation and gene expression levels showed consistent change patterns upon RK treatment. Our study provides a new perspective for understanding the hypoglycemic mechanism of RK and may be helpful for investigating the modes of action of hypoglycemic drugs using the zebrafish hyperglycemia model.