Molecular mechanisms of Momordica charantia saponins in improving insulin resistance in common carp (Cyprinus carpio)

Insulin resistance (IR) is a common, serious and typical concomitant state induced by high-carbohydrate diets for fish, which has limited the role of carbohydrate in protein-sparing effect for fish including common carp (Cyprinus carpio). Our preliminary study demonstrates the potential of Momordica charantia saponin (MCS) as a therapeutic additive for common carp hepatopancreas IR, but the mechanism needs further excavation. Hence, this study focused on the underlying molecular mechanisms of MCS in ameliorating IR. MiR-29a overexpression and silencing models were established via in intraperitoneal injection. Therewith, the miR-29a injection intervention at a 14-day interval was conducted for common carp fed with high-carbohydrate diets containing MCS. MiR-29a mimics intervention significantly reduced mass gain rate and increased feed conversion ratio. Histologically, hepatopancreas after miR-29a mimics injection presented the signature features of necroptosis. MiR-29a mimics injection not only caused a significant decrease in hepatopancreas glycogen synthesis and an increase in hepatopancreas lipids, but also induced abnormal serum lipids. Mechanistically, miR-29a mimics injection restrained activity of insulin signaling pathway through significantly down-regulating the gene and protein expressions of phosphoinositide 3-kinase 1 (pik3r1), thereby leading to decreasing glycolysis and glycogen synthesis and increasing gluconeogenesis and glycogenolysis. MiR-29a inhibitor intervention could assist MCS to promote the carbohydrate utilization ability. Overall, MCS ameliorates hepatopancreas IR and enhances the carbohydrate metabolism through activation of the insulin signal pathway via miRNA-29a targeting pik3r1. From the perspective of the carbohydrate utilization improvement of fish, the results broaden the horizon for the development of miRNA-based additives.