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This could explain discrepancies about the role of vagal gut\u2010brain signalling in long\u2010term control of energy balance. Here we use a validated approach to selectively ablate sensory vagal neurones that innervate the gut to determine the role of vagal gut\u2010brain signalling in the control of food intake, energy expenditure and glucose homoeostasis in response to different diets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Rat nodose ganglia were injected bilaterally with either the neurotoxin saporin conjugated to the gastrointestinal hormone cholecystokinin (CCK), or unconjugated saporin as a control. Food intake, body weight, glucose tolerance and energy expenditure were measured in both groups in response to chow or high\u2010fat high\u2010sugar (HFHS) diet. Willingness to work for fat or sugar was assessed by progressive ratio for orally administered solutions, while post\u2010ingestive feedback was tested by measuring food intake after an isocaloric lipid or sucrose pre\u2010load.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Vagal deafferentation of the gut increases meal number in lean chow\u2010fed rats. Switching to a HFHS diet exacerbates overeating and body weight gain. The breakpoint for sugar or fat solution did not differ between groups, suggesting that increased palatability may not drive HFHS\u2010induced hyperphagia. Instead, decreased satiation in response to intra\u2010gastric infusion of fat, but not sugar, promotes hyperphagia in CCK\u2010Saporin\u2010treated rats fed with HFHS diet.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We conclude that intact sensory vagal neurones prevent hyperphagia and exacerbation of weight gain in response to a HFHS diet by promoting lipid\u2010mediated satiation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/apha.13530","type":"journal-article","created":{"date-parts":[[2020,6,30]],"date-time":"2020-06-30T21:38:53Z","timestamp":1593553133000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Intact vagal gut\u2010brain signalling prevents hyperphagia and excessive weight gain in response to high\u2010fat high\u2010sugar diet"],"prefix":"10.1111","volume":"231","author":[{"given":"Molly","family":"McDougle","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics University of Florida Gainesville FL USA"},{"name":"Center for Integrative Cardiovascular and Metabolic Disease University of Florida Gainesville FL USA"},{"name":"The John B. 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