Mu-opioid receptors put brakes on appetite

By Eleanor McDermid

Activation of mu-opioid receptors (MORs) in the nerves of the portal vein walls triggers a gut-brain neural circuit that leads to feelings of satiety, researchers report in Cell.

"The regulatory role of MORs in the control of food intake has been largely documented for the central nervous system, related to their roles in the so-called 'reward system,' " they write. "Here, we report that MORs play a role in mediating the satiety effects of alimentary proteins, acting within a neural gut-brain circuit."

It is already known that satiety arises on induction of intestinal gluconeogenesis, which leads to the release of glucose into the portal vein (which collects blood from the whole gut) and a decrease in hunger. This system is strongly triggered by a protein-enriched diet.

Gilles Mithieux (INSERM, Lyon, France) and team now demonstrate the crucial role of portal vein neural system in this process; they show that inactivating these nerves in rats with capsaicin prevents induction of intestinal gluconeogenesis in response to a protein-enriched diet.

When food proteins are digested, they produce oligopeptides that have mu-opioid activity - β1-7 in the case of caseins from milk. Mithieux et al found that, when directly infused into the portal veins of rats, β1-7 or a selective MOR agonist significantly suppressed intestinal gluconeogenesis, whereas MOR antagonists upregulated it.

Newly synthesized glucose appeared in the portal vein in response to MOR antagonist treatment and this was accompanied by activation of brain areas that receive signals from the portal area, and by decreased appetite in the rats.

Infusion of MOR antagonists did not further enhance intestinal gluconeogenesis in rats fed a protein-enriched diet, indicating that MOR antagonists and protein act via the same pathway. In keeping with this, infused peptones from milk or meat digestion suppressed gluconeogenesis - unless the portal nerves had been deactivated with capsaicin treatment.

Infusion of digestive peptones suppressed gluconeogenesis in wild-type mice, but not in mice lacking the gene encoding MORs. When the mice were switched from a starch- to a protein-enriched diet, wild-type mice reduced their food intake by about 20%, but no such effect occurred in the mice lacking MORs.

"As MOR-positive neural fibers are present in the wall of the human portal vein branches, the mechanisms uncovered here may also take place in humans," say Mithieux et al.

They add: "This knowledge may thus pave the way for future approaches in the treatment and/or prevention of metabolic diseases."

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