Vagal afferents are essential for resection‐induced intestinal growth in association with GLP‐2‐induced activation of vagal afferents in the nucleus tract solitary (NTS)

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent proglucagon-derived hormone that stimulates intestinal growth through poorly understood paracrine and/or neural pathways. The relationship between GLP-2 action and a vagal pathway is unclear. Our aims were to determine whether 1) the GLP-2 receptor (GLP-2R) is expressed on vagal afferents by localizing it to the nodose ganglia; 2) exogenous GLP-2 stimulates the vagal afferent pathway by determining immunoreactivity for c-fos protein in the nucleus of the solitary tract (NTS); and 3) functional ablation of vagal afferents attenuates GLP-2-mediated intestinal growth in rats maintained with total parenteral nutrition (TPN). A polyclonal antibody against the N terminus of the rat GLP-2R was raised and characterized. The GLP-2R was localized to vagal afferents in the nodose ganglia and confirmed in enteroendocrine cells, enteric neurons, and nerve fibers in the myenteric plexus using immunohistochemistry. Activation of the vagal afferent pathway, as indicated by c-fos protein immunoreactivity in the NTS, was determined by immunohistochemistry after ip injection of 200 μg human GLP-2. GLP-2 induced a significant 5-fold increase in the number of c-fos protein immunoreactive neurons in the NTS compared with saline. Ablation of vagal afferent function by perivagal application of capsaicin, a specific afferent neurotoxin, abolished c-fos protein immunoreactivity, suggesting that activation of the NTS due to GLP-2 is dependent on vagal afferents. Exogenous GLP-2 prevented TPN-induced mucosal atrophy, but ablation of vagal afferent function with capsaicin did not attenuate this effect. This suggests that vagal-independent pathways are responsible for GLP-2 action in the absence of luminal nutrients during TPN, possibly involving enteric neurons or endocrine cells. This study shows for the first time that the GLP-2R is expressed by vagal afferents, and ip GLP-2 activates the vagal afferent pathway.

Download Full-text

Faculty Opinions recommendation of Epimorphin(-/-) mice have increased intestinal growth, decreased susceptibility to dextran sodium sulfate colitis, and impaired spermatogenesis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.14144.471648 ◽

2006 ◽

Author(s):

Kim Barrett

Keyword(s):

Sodium Sulfate ◽

Dextran Sodium Sulfate ◽

Intestinal Growth

Download Full-text

Learning of food preferences: mechanisms and implications for obesity & metabolic diseases

International Journal of Obesity ◽

10.1038/s41366-021-00894-3 ◽

2021 ◽

Author(s):

Hans-Rudolf Berthoud ◽

Christopher D. Morrison ◽

Karen Ackroff ◽

Anthony Sclafani

Keyword(s):

Metabolic Diseases ◽

Food Preferences ◽

Reward System ◽

Nutrient Sensing ◽

Vagal Afferents ◽

Dietary Knowledge ◽

Ongoing Work ◽

Brain Reward ◽

The Brain ◽

Vagal Function

AbstractOmnivores, including rodents and humans, compose their diets from a wide variety of potential foods. Beyond the guidance of a few basic orosensory biases such as attraction to sweet and avoidance of bitter, they have limited innate dietary knowledge and must learn to prefer foods based on their flavors and postoral effects. This review focuses on postoral nutrient sensing and signaling as an essential part of the reward system that shapes preferences for the associated flavors of foods. We discuss the extensive array of sensors in the gastrointestinal system and the vagal pathways conveying information about ingested nutrients to the brain. Earlier studies of vagal contributions were limited by nonselective methods that could not easily distinguish the contributions of subsets of vagal afferents. Recent advances in technique have generated substantial new details on sugar- and fat-responsive signaling pathways. We explain methods for conditioning flavor preferences and their use in evaluating gut–brain communication. The SGLT1 intestinal sugar sensor is important in sugar conditioning; the critical sensors for fat are less certain, though GPR40 and 120 fatty acid sensors have been implicated. Ongoing work points to particular vagal pathways to brain reward areas. An implication for obesity treatment is that bariatric surgery may alter vagal function.

Download Full-text

Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. R448-R455 ◽

Cited By ~ 25

Author(s):

Jason Wright ◽

Carlos Campos ◽

Thiebaut Herzog ◽

Mihai Covasa ◽

Krzysztof Czaja ◽

...

Keyword(s):

Nmda Receptor ◽

Food Intake ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Fourth Ventricle ◽

Nmda Receptor Antagonist ◽

Behavioral Pattern ◽

Vagal Afferents ◽

Nmda Receptor Antagonists ◽

The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

Download Full-text

Control of breathing in anesthetized dogs by a left-heart baroreflex

Journal of Applied Physiology ◽

10.1152/jappl.1986.61.6.2095 ◽

1986 ◽

Vol 61 (6) ◽

pp. 2095-2101 ◽

Cited By ~ 4

Author(s):

T. C. Lloyd

Keyword(s):

Pulmonary Veins ◽

Vagal Afferents ◽

Low Flow ◽

Base Line ◽

Left Heart ◽

Breathing Frequency ◽

Autonomic Ganglion ◽

Anesthetized Dogs ◽

The Right ◽

Vagal Cooling

Anesthetized open-chest dogs on cardiopulmonary bypass were used to test the hypothesis that breathing reflexly responds to distension of the left-heart chambers. Bypass perfusion withdrew systemic flow from the right atrium and returned it to the aorta after gas exchange. Ventricles were fibrillated. The left heart was isolated by tying all pulmonary veins, and it was perfused separately at low flow admitted through one pulmonary vein and withdrawn from the ventricle. Left-heart pressure was intermittently raised abruptly from a nominal base line of 0 by partial occlusion of outflow. Pressures from approximately 10 to 50 cmH2O caused proportional increases in breathing frequency and decreases in expiratory and inspiratory times. Changes occurred immediately, reached a plateau within approximately 20 s, and were sustained for periods of observation as long as 3 min. Recovery to base line followed stimulus removal. Vagal cooling to 8 degrees C prevented responses, but autonomic ganglion blockade with hexamethonium had no effect. I conclude that breathing may be stimulated by left-heart distension and that this is mediated by large myelinated vagal afferents.

Download Full-text

High-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and cholecystokinin: implications for circulatory control

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01156.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. H961-H967 ◽

Cited By ~ 8

Author(s):

Jackie M. Y. How ◽

Barbara C. Fam ◽

Anthony J. M. Verberne ◽

Daniela M. Sartor

Keyword(s):

Arterial Pressure ◽

High Fat Diet ◽

Cardiovascular Effects ◽

Vagal Afferents ◽

Sprague Dawley ◽

High Fat ◽

Lower Plasma ◽

Lower Tertile ◽

Circulatory Control ◽

Plasma Leptin

Gastric leptin and cholecystokinin (CCK) act on vagal afferents to induce cardiovascular effects and reflex inhibition of splanchnic sympathetic nerve discharge (SSND) and may act cooperatively in these responses. We sought to determine whether these effects are altered in animals that developed obesity in response to a medium high-fat diet (MHFD). Male Sprague-Dawley rats were placed on a low-fat diet (LFD; n = 8) or a MHFD ( n = 24) for 13 wk, after which the animals were anesthetized and artificially ventilated. Arterial pressure was monitored and blood was collected for the determination of plasma leptin and CCK. SSND responses to leptin (15 μg/kg) and CCK (2 μg/kg) administered close to the coeliac artery were evaluated. Collectively, MHFD animals had significantly higher plasma leptin but lower plasma CCK levels than LFD rats ( P < 0.05), and this corresponded to attenuated or reversed SSND responses to CCK (LFD, −21 ± 2%; and MHFD, −12 ± 2%; P < 0.05) and leptin (LFD, −6 ± 2%; and MHFD, 4 ± 1%; P < 0.001). Alternatively, animals on the MHFD were stratified into obesity-prone (OP; n = 8) or obesity-resistant (OR; n = 8) groups according to their weight gain falling within the upper or lower tertile, respectively. OP rats had significantly higher resting arterial pressure, adiposity, and plasma leptin but lower plasma CCK compared with LFD rats ( P < 0.05). The SSND responses to CCK or leptin were not significantly different between OP and OR animals. These results demonstrate that a high-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and CCK and may impact on sympathetic vasomotor mechanisms involved in circulatory control.

Download Full-text