Dietary Carbohydrates but Not Proteins Are the Main Nutritional Determinant of FGF21 Production in Mice

Abstract

Fibroblast growth factor 21 (FGF21) is a polypeptide secreted by the liver and involved in various metabolic processes, such as ketogenesis, lipid oxidation, thermogenesis and white adipose tissue browning. Nutritional mechanisms controlling its secretion are poorly understood. The aim of the present study was to investigate the influence of changes in the protein to carbohydrate ratio in the diet on FGF21 synthesis and secretion by the liver and the subsequent impact on energy metabolic pathways.25 male C57BL/6 mice aged 7 weeks were divided into 3 groups (n = 8–9/group) and fed during three weeks with a low‐protein/high‐carb diet (LPHC), a normo‐protein/normo‐carb diet (NPNC) or a high‐protein/low‐carb diet (HPLC). Food intake and body weight were measured throughout the experiment. At the end of the first week, the thermogenic response to feeding (TEF) was followed during 6 hours after ingestion of a 1g‐calibrated meal of their test‐diet given after an overnight fast. At the end of the experiment, the same test‐meal procedure was repeated and mice were killed four hours latr, for measurement of gene expression in liver, brown and epidydymal adipose tissues. In parallel with this in vivo experiment, primary cultures of rat hepatocytes were conducted to measure the specific effects of amino acids, leucine and glucose in the presence or absence of insulin and/or glucagon on the synthesis of FGF21.Plasma FGF21 measured 4 hours after ingestion of the test‐meals was positively correlated with the carbohydrate content of the diet. Consumption of LPHC and HPLC diets increased TEF but with different kinetics compared to the NPNC diet. In LPHC‐fed mice expression of UCP2 in the epididymal adipose was increased while in HPLC‐fed mice, ketogenesis, measured before ingestion of the test‐meal (fasted state), was increased. In primary cultured of hepatocytes high glucose concentrations in the presence of insulin increased FGF21 synthesis. Amino acid or leucine alone had no effect on FGF21 synthesis, glucagon decreased FGF21 synthesis and this last effect was antagonized by insulin.These results indicate that FGF21 synthesis is stimulated by carbohydrate and glucose but not protein and amino acid. Therefore, the increased TEF observed in response to ingestion of the LPHC diet was probably mediated by FGF21 whereas the influence of HPLC diet on fasting ketogenesis and TEF did not involve FGF21.