Introduction: The interactions between glucose and energy homeostasis are well known, especially regarding the suppressing role on food intake of glucose into the portal vein. Material and Methods: The expression of genes of gluconeogenesis was characterized at the level of mRNA, protein, and enzymatic activity. Intestinal glucose production was quantified using a combination of (3- 3H) glucose tracer dilution and arterio-venous glucose balance. The effect of portal glucose on food intake was studied using conscious rats with indwelling catheters into the portal vein. The effect of infusions at the hypothalamus level was studied by immunodetection of the protein c-Fos. Results: All regulatory genes of gluconeogenesis are expressed in the small intestine from rat and human. They are strongly induced in rat: during fasting; and by protein-enriched diet. In both cases, this promotes glucose release in the portal vein, lasting after the postprandial period for the protein-enriched regimen. The infusion of glucose at comparable rates into the portal vein decreases food intake in rat, and activates the hypothalamic regions involved in the control of food intake, just as does the protein enriched diet. Conclusion: These results provide a mechanistic explanation for the effect of satiety induced by diet protein, well known to occur in animals and humans, but unsolved up to now.