["Acta Physiologica, Volume 231, Issue 3, March 2021. ", "\nAbstract\n\nAim\nThe tools that have been used to assess the function of the vagus nerve lack specificity. This could explain discrepancies about the role of vagal gut‐brain signalling in long‐term 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‐brain signalling in the control of food intake, energy expenditure and glucose homoeostasis in response to different diets.\n\n\nMethods\nRat 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‐fat high‐sugar (HFHS) diet. Willingness to work for fat or sugar was assessed by progressive ratio for orally administered solutions, while post‐ingestive feedback was tested by measuring food intake after an isocaloric lipid or sucrose pre‐load.\n\n\nResults\nVagal deafferentation of the gut increases meal number in lean chow‐fed 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‐induced hyperphagia. Instead, decreased satiation in response to intra‐gastric infusion of fat, but not sugar, promotes hyperphagia in CCK‐Saporin‐treated rats fed with HFHS diet.\n\n\nConclusions\nWe conclude that intact sensory vagal neurones prevent hyperphagia and exacerbation of weight gain in response to a HFHS diet by promoting lipid‐mediated satiation.\n\n"]