Intestinal gluconeogenesis is involved in the control of food intake. We show that mu-opioid receptors (MORs) present in nerves in the portal vein walls respond to peptides to regulate a gut-brain neural circuit that controls intestinal gluconeogenesis and satiety. In vitro, peptides and protein digests behave as MOR antagonists in competition experiments. In vivo, they stimulate MOR-dependent induction of intestinal gluconeogenesis via activation of brain areas receiving inputs from gastrointestinal ascending nerves. MOR-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets. Portal infusions of MOR modulators have no effect on food intake in mice deficient for intestinal gluconeogenesis. Thus, the regulation of portal MORs by peptides triggering signals to and from the brain to induce intestinal gluconeogenesis are links in the satiety phenomenon associated with alimentary protein assimilation.