Interactions between dietary carbohydrate and metformin: Implications on energy sensing, insulin signaling pathway, glycolipid metabolism and glucose tolerance in blunt snout bream Megalobrama amblycephala

Abstract

A 12-week feeding trial was performed to evaluate the effects of metformin on growth performance, energy sensing, insulin signaling pathway, glycolipid metabolism and glucose tolerance of blunt snout bream fed high-carbohydrate diets. Fish were randomly fed four diets containing two dietary carbohydrate levels (30 and 43%) and two metformin levels (0 and 0.25%). High carbohydrate levels remarkably increased tissue glycogen and lipid contents, hepatic adenosine triphosphate (ATP) and adenosine monophosphate (AMP) contents and the ATP/AMP ratio, plasma levels of glucose, insulin, triglyceride, glycated serum protein (GSP), advanced glycation end products (AGES) and lactic acid, hepatic t-AMPK protein levels and the transcriptions of AMPKα1, AMPKα2, target of rapamycin (TOR), insulin receptor (IR), ribosomal protein S6 kinase-polypeptide 1 (S6K1), glucokinase (GK), pyruvate kinase (PK), glucose transporter 2 (GLUT 2), glycogen synthase (GS), acetyl-CoA carboxylase α (ACCα), fatty acid synthase (FAS) and sterol regulatory element-binding protein-1 (SREBP1), whereas the opposite was true for weight gain, relative feed intake (RFI), feed conversion ratio (FCR), pyruvate levels, p-AMPK level, p-AMPK/t-AMPK ratio and the transcriptions of insulin receptor substrate 1 (IRS1), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), fructose-1,6-biphosphatase (FBPase), carnitine palmitoyltransferase IA (CPT IA), peroxisome proliferator activated receptor α (PPARα) and acyl-CoA oxidase (ACO). In addition, metformin supplementation remarkably increased tissue glycogen contents, plasma lactic acid level, hepatic AMP content, t-AMPK and p-AMPK level, p-AMPK/t-AMPK ratio and the transcriptions of AMPKα1, AMPKα2, IR, IRS1, GK, PK, GLUT 2, GS, CPT IA, PPARα and ACO, while the opposite was true for the remaining indicators. Significant interactions between dietary carbohydrate and metformin were also observed in RFI, FCR, tissue glycogen and lipid contents, hepatic ATP/AMP ratio, plasma metabolites, the phosphorylation of AMPK and the transcriptions of TOR, IRS1, S6K1, PK, G6Pase, GLUT 2, GS, ACCα, FAS, SREBP1, CPT IA, PPARα and ACO. Furthermore, metformin improved the glucose tolerance of fish fed high-carbohydrate diets after glucose loading. Overall, our findings indicated that metformin should be benefits the intermediary metabolism of Megalobrama amblycephala fed high-carbohydrate diets through the enhancement of energy sensing, insulin sensitivity, glycolysis, glycogenesis and fatty acid oxidation coupled with the suppression of gluconeogenesis and lipogenesis.