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      The vagus nerve mediates the physiological but not pharmacological effects of PYY 3-36 on food intake

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          Abstract

          Peptide YY (PYY 3-36) is a post-prandially released gut hormone with potent appetite-reducing activity, the mechanism of action of which is not fully understood. Unravelling how this system physiologically regulates food intake may help unlock its therapeutic potential, whilst minimising unwanted effects. Here we demonstrate that germline and post-natal targeted knockdown of the PYY 3-36 preferring receptor (neuropeptide Y (NPY) Y2 receptor (Y2R)) in the afferent vagus nerve is required for the appetite inhibitory effects of physiologically-released PYY 3-36, but not peripherally administered pharmacological doses. Post-natal knockdown of the Y2R results in a transient body weight phenotype that is not evident in the germline model. Loss of vagal Y2R signalling also results in altered meal patterning associated with accelerated gastric emptying. These results are important for the design of PYY-based anti-obesity agents.

          Highlights

          • A quarter of vagal afferent neurones express the NPY Y2 receptor (Y2R).

          • Loss of vagal afferent Y2R abrogates the anorectic effects of low dose but not high dose PYY 3-36.

          • Loss of vagal Y2R accelerates gastric emptying and alters meal patterning, leading to smaller, faster and more frequent meals.

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          Most cited references38

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          A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management.

          Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously.
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            A gut-brain neural circuit for nutrient sensory transduction

            The brain is thought to sense gut stimuli only via the passive release of hormones. This is because no connection has been described between the vagus and the putative gut epithelial sensor cell—the enteroendocrine cell. However, these electrically excitable cells contain several features of epithelial transducers. Using a mouse model, we found that enteroendocrine cells synapse with vagal neurons to transduce gut luminal signals in milliseconds by using glutamate as a neurotransmitter. These synaptically connected enteroendocrine cells are referred to henceforth as neuropod cells. The neuroepithelial circuit they form connects the intestinal lumen to the brainstem in one synapse, opening a physical conduit for the brain to sense gut stimuli with the temporal precision and topographical resolution of a synapse.
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              Sensory Neurons that Detect Stretch and Nutrients in the Digestive System.

              Neural inputs from internal organs are essential for normal autonomic function. The vagus nerve is a key body-brain connection that monitors the digestive, cardiovascular, and respiratory systems. Within the gastrointestinal tract, vagal sensory neurons detect gut hormones and organ distension. Here, we investigate the molecular diversity of vagal sensory neurons and their roles in sensing gastrointestinal inputs. Genetic approaches allowed targeted investigation of gut-to-brain afferents involved in homeostatic responses to ingested nutrients (GPR65 neurons) and mechanical distension of the stomach and intestine (GLP1R neurons). Optogenetics, in vivo ganglion imaging, and genetically guided anatomical mapping provide direct links between neuron identity, peripheral anatomy, central anatomy, conduction velocity, response properties in vitro and in vivo, and physiological function. These studies clarify the roles of vagal afferents in mediating particular gut hormone responses. Moreover, genetic control over gut-to-brain neurons provides a molecular framework for understanding neural control of gastrointestinal physiology.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                08 February 2024
                March 2024
                08 February 2024
                : 81
                : 101895
                Affiliations
                [1 ]Section of Investigative Medicine and Endocrinology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
                [2 ]School of Medicine, Faculty of Health, Education, Medicine & Social Care, Anglia Ruskin University, Chelmsford, CM1 1SQ, United Kingdom
                [3 ]Department of Bioengineering, Imperial College London, London, United Kingdom
                [4 ]Medical Research Council Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, United Kingdom
                [5 ]Neuroscience Division, Garvan Institute of Medical Research, Darlinghurst, Australia
                [6 ]Department of Health Sciences and Technology, ETH Zurich, Schwerzenbach, Switzerland
                [7 ]Imperial College Business School, Imperial College London, United Kingdom
                Author notes
                []Corresponding author. Section of Investigative Medicine and Endocrinology, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom. v.salem@ 123456imperial.ac.uk
                Article
                S2212-8778(24)00026-7 101895
                10.1016/j.molmet.2024.101895
                10877939
                38340808
                3c524653-4779-4655-b3b2-772ff24492c7
                © 2024 Published by Elsevier GmbH.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 26 November 2023
                : 25 January 2024
                : 2 February 2024
                Categories
                Original Article

                vagus nerve,pyy,appetite,gut hormones
                vagus nerve, pyy, appetite, gut hormones

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