To determine the mechanism of meal regulated synthesis of pancreatic digestive enzymes , we studied the effect of fasting and re-feeding on pancreatic protein synthesis, relative mRNA levels of digestive enzymes and activation of the translational machinery. Utilizing the flooding dose technique with ³H-_L-phenylalanine, morning protein synthesis in the pancreas of ICR mice fed ad libitum was 7.9 ± 0.3 nmol phe/mg prot/10 min. Prior fasting for 18 h reduced total protein synthesis to 70 ± 1.4 % of this value. Re-feeding 2h, during which the mice consumed 29% of their daily food intake, increased protein synthesis to 117.3 ± 4.9 % of the control level. Pancreatic mRNA levels of amylase, lipases, trypsins, chymotrypsin, elastases, as well as that for several housekeeping genes tested were not significantly changed after re-feeding when compared to fasted mice. By contrast, the major translational control pathway involving Akt, mTOR and S6K was strongly regulated by fasting and re-feeding. Fasting 18 h decreased phosphorylation of ribosomal protein S6 to almost undetectable levels and re-feeding highly increased it. The most highly phosphorylated form of the eIF4E Binding Protein (4E-BP1) made up the 14.6 % of total 4E-BP1 in normally fed animals, only to 2.8 % after fasting, and was increased to 21.4 % after re-feeding. This was correlated with an increase in the formation of the eIF4E-eIF4G complex after re-feeding. By contrast, feeding did not affect eIF2B activity. Thus, food intake stimulates pancreatic protein synthesis, and translational effectors without increasing digestive enzyme mRNA levels.