III. Gastrointestinal and vagal detection of nutrients

Food intake is regulated by hormonal and physical sensation signals from the gastrointestinal tract. Food ingestion notably induces gastric distension, changes in gut motility, and release of several gastrointestinal hormones, such as ghrelin, cholecystokinin (CCK), peptide YY3-36 (PYY3-36), and glucagon-like peptide-1 (GLP-1). The enteric neural system plays a role in the transmission of the physical sensation from the gastrointestinal tract to the brain, but also in the central and systemic effects of these hormones. Disruption of afferent vagal-brain communication markedly suppresses the control of food intake mediated by gastrointestinal hormones. Recent data demonstrate a crucial role of vagal-brain communications in the transmission of regulatory signals produced by specific nutrients.
Glutamate and aspartate are amino acid neurotransmitters that have a unique taste, known as the “umami” taste. Glutamate is first detected during mastication in the mouth, and this oral stimulus is transmitted to the NTS through the autonomic facial, glossopharyngeal, and vagal nerves. This signal is part of the cephalic phase of digestion preparing the body to eat. Second, glutamate sensing takes place in the stomach and is transmitted to the brain by vagal afferent fibers. Functional magnetic resonance imaging demonstrates that detection of glutamate in the stomach leads to a specific activation of brain areas regulating learning, emotion, and memory (hippocampus and amygdala), and of areas controlling thermogenesis (DMN of the hypothalamus and medial pre-optic area). Unlike glucose, glutamate sensing in the stomach does not activate brain centers involved in reward and addiction. Brain activation by glutamate is abolished by subdiaphragmatic total vagotomy. Since glutamate is completely metabolized by the intestine, glutamate sensing is restricted to the gastrointestinal tract. Glutamate is detected by its binding to the metabotropic glutamate receptor type 1 in mucus cells. Mucus cells expressing NO synthase release NO on their basal sides inducing the release of serotonin from enterochromaffin cells and the further activation of the vagal digestive secretions to improve food digestion and increase nutrient absorption. A role of glutamate sensing in the regulation of energy homeostasis has recently been demonstrated.
Rats fed a high-fat diet containing 1% glutamate were resistant to the development of obesity and harbored lower fat deposits, with reduced circulating leptin levels. Functional magnetic resonance imaging suggests that glutamate sensing likely induces thermogenesis and this additional energy expenditure prevents fat deposition and obesity (Figure 6). (Kunio Torii, Lecture) Vagal brain communications are also crucial for the maintenance of essential amino acid homeostasis. The central nervous system is able to identify the sensory characteristics of a food deficient in an essential amino acid such as lysine. Following the detection of lysine deficiency, the brain develops a specific behavior resulting in motivation to eat other foods that potentially contain lysine. This detection is linked to the induction of the sensitivity of the afferent vagal hepatic branches to lysine. The presence of lysine in the stomach induces the activation of the hippocampus and the hypothalamus, more particularly the LHA. Lysine deficiency results in an increase in the magnitude of this activation and in the activation of other brain areas. Notably, lysine deficiency results in the appearance of lysine-sensitive neurons in the nucleus
accumbens. The nucleus accumbens is connected to the VMA, which is involved in the regulation of the motivation to eat. This mechanism could be linked to the development of the motivational behavior induced by a lysine-deficient diet. Moreover, neural plasticity of specific neurons of the LHA allows the CNS to associate environmental (sound), sensory (smell, taste), and digestive (visceral information) characteristics with lysine-deficient food. This plasticity is induced by the activation of activin nerve. This activation of the autonomic nervous system by glutamate sensing induces A in the olfactory bulb (smell), LHA (feeding), the median eminence of the hypothalamus, and the NTS (tastes and visceral information). Interestingly, the neurons of the LHA that become sensitive to lysine were previously activated by glutamate (Kunio Torii, Lecture). The anatomic location of the portal vein makes this area highly suitable for nutrient sensing. An increase in portal glucose levels induces a decrease in food intake, changes in food preference, and an improvement in hepatic insulin sensitivity.
Portal glucose sensing is also involved in the detection of slow developing hypoglycemia. Portal glucose sensing depends on afferent vagal nerve stimulation, where glucose is detected in the wall of the portal vein and induces a signal transmitted to the brainstem by both vagal and spinal afferents. A high glucose level in the portal vein seems to be detected by Glut2, whereas low glucose is detected via its binding to SGLT3 (Gilles Mithieux, Lecture).
Sensors present in the portal vein are also involved in the inhibition of food intake induced by a protein-enriched diet. Oligopeptides derived from the digestion of dietary protein are delivered to the portal blood. These peptides have an antagonistic effect on the μ-opioid receptors present in the portal nervous system and activate brain regions receiving inputs from both the vagal afferents (DVC) and the spinal afferents (PBN), and the hypothalamic nuclei regulating food intake (PVN). This in turn induces the expression of gluconeogenic genes (glucose-6-phosphatase and phosphoenol-pyruvate carboxykinase) in the intestine and the further release of glucose in the portal vein. This glucose is then detected by the glucose sensor SGLT3 and induces a decrease in food intake. In summary, proteins act indirectly on food intake by inducing intestinal gluconeogenesis and its sensing by the portal glucose sensor (Figure 7A and C). Proteins reduce food intake by a mechanism independent of the melanocortinergic pathway, as paradoxically, a protein-enriched diet induces increased expression of orexigenic AgRP and decreased expression of the anorexigenic POMC protein (Gilles Mithieux, Lecture).
Dietary fiber improves insulin sensitivity and glucose tolerance in lean and obese subjects. In the distal gut, soluble dietary fiber is fermented by the microbiota into short-chain fatty acids (acetate, propionate, and butyrate). Propionate and butyrate both stimulate intestinal glucose release by inducing the expression of gluconeogenic enzymes in the intestine and in the colon. In addition, propionate is used as a substrate for glucose production. Butyrate induces gene expression by increasing cAMP levels in enterocytes, which is known to induce the expression of gluconeogenic genes. As oligopeptides, propionate induces gluconeogenic gene expression indirectly via a portal-brain neural circuit initiated by agonist binding to the fatty acid receptor FFAR3. The causal role of intestinal gluconeogenesis in the beneficial effect of protein or fiber has been confirmed by the use of intestinal gluconeogenesis−deficient mice (Figure 7B and C). Moreover, using these mice confirms that even if the microbiota is important for the conversion of fiber into short-chain fatty acids, the changes in microbiota composition per se have play no role in the beneficial effect of dietary fiber (Gilles Mithieux, Lecture).
These recent data highlight the key role of the portal glucose signaling in nutrient sensing by the brain. Nutrient sensing by the portal nervous system induces a reflex arc with the brain, thus inducing intestinal gluconeogenesis. Portal glucose sensing might thus be related to a prolonged effect of hunger sensation, namely a “satiety” phenomenon, rather than to a “satiation” phenomenon.

“Neural Orchestration of Metabolism and Islet function”
I. General points on the central control of energy balance and food intake
II. Mechanisms of direct detection of nutrients and hormones by the brain
III. Gastrointestinal and vagal detection of nutrients
IV. Control of β-cell function by the brain
V. Conclusion
References
Lectures during IGIS meeting