Dietary poly-β-hydroxybutyrate optimized by dose-response screening, mitigated high-carbohydrate diet-induced glucose...

To investigate the potential of poly-β-hydroxybutyrate (PHB) to alleviate high-carbohydrate diets-induced growth inhibition and glucose metabolism disorder in topmouth culter (Culter alburnus), this study was design a dose-response trial to determine the appropriate PHB level for topmouth culter by assessing growth and glucose metabolism, and a validation trial to evaluate the capacity of the appropriate PHB level to alleviate high-carbohydrate diets-induced growth inhibition and glucose metabolic dysfunction. The results of dose-response trial showed that 2% PHB improved growth performance and glucose homeostasis, whereas 8% PHB had adverse effects, thus identifying 2% PHB as the appropriate level for topmouth culter. The results of validation trial demonstrated that high-carbohydrate diets suppressed the growth performance (FW, WGR, SGR and FE) (p<0.05), resulted in an elevation in the levels of serum AST, ALT, LDH, GLU, INS, TG and TC (p<0.05). The topmouth culter in high-carbohydrate group exhibited insulin resistance (increased HOMA-IR), impaired glucose tolerance, and abnormal hepatopancreatic glycogen synthesis. After supplementation with 2% PHB, these above indicators were significantly reversed: growth performance was improved, serum metabolic parameters (GLU, INS, TG, and TC) and hepatopancreatic injury markers (AST and ALT) were reduced, insulin sensitivity was enhanced, glucose clearance rate was accelerated (p<0.05). Meanwhile, high-carbohydrate diets up-regulated the levels of G6Pase, PEPCK, PFK and FBA, down-regulated the levels of HK, PK, GCS and GPa (p<0.05), while 2% PHB effectively reversed these changes, including lessening the levels of G6Pase and PEPCK, and enhancing the levels of HK and GCS (p<0.05). Noteworthy, high-carbohydrate diets-induced the changes in glycogen content and GPa were further promoted by 2% PHB (p<0.05). High-carbohydrate diets inhibited the levels of p-AKT (Ser473) and p-GSK3β (Ser9) proteins in hepatopancreas (p<0.05), while PHB effectively activated the AKT/GSK3β signaling pathway (p<0.05). Transcriptomic analysis revealed that PHB regulated key metabolic pathways, including the insulin signaling pathway, PPAR signaling pathway, and steroid hormone biosynthesis. Metabolomic results indicated that PHB improved metabolic regulation and physiological adaptation to high-carbohydrate diets by regulating cortisol synthesis and secretion, and vitamin digestion and absorption. In conclusion, dietary 2% PHB improved insulin sensitivity, enhanced glucose utilization capacity by triggering the AKT/GSK3β signaling pathway in topmouth culter, thereby alleviating high-carbohydrate diets-induced-growth inhibition and glucose metabolism disorders. These findings offered scientific support for the use of PHB as a functional feed additive to improve carbohydrate utilization and conserve protein resources in fish.