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However, for reasons that are incompletely understood, in preclinical and clinical studies, adding either a GIPR agonist or GIPR antagonist to GLP-1R agonism causes additional weight loss\n                    <jats:sup>1<\/jats:sup>\n                    . Here we show that distinct brain regions mediate the appetite-suppressing effects of GIPR agonists and the synergistic weight loss effects conferred by GIPR antagonists. We knock out\n                    <jats:italic>Gipr<\/jats:italic>\n                    in either the area postrema (AP) or hypothalamus of mice (Gipr\n                    <jats:sup>AP-KO<\/jats:sup>\n                    and Gipr\n                    <jats:sup>hypo-KO<\/jats:sup>\n                    , respectively) and compare body weight and food intake responses to GIPR agonists and antagonists, alone and in combination with the GLP-1R agonist liraglutide. Gipr\n                    <jats:sup>AP-KO<\/jats:sup>\n                    mice exhibit partial protection against diet-induced obesity, reduced responsiveness to the appetite-suppressing effects of acyl-GIP and a reduced ability of acyl-GIP to prevent avoidance triggered by peptide YY. Weight loss effects of liraglutide are comparable in Gipr\n                    <jats:sup>AP-KO<\/jats:sup>\n                    and control mice, and the co-administration of a GIPR antagonist peptide causes similar additional weight loss in both groups. Gipr\n                    <jats:sup>hypo-KO<\/jats:sup>\n                    mice, by contrast, exhibit normal appetite suppression by acyl-GIP but enhanced weight loss on liraglutide compared with control mice. Gipr\n                    <jats:sup>hypo-KO<\/jats:sup>\n                    also abolishes the synergistic effect of a GIPR antagonist when combined with liraglutide\u2014an effect that is not mediated by nucleus tractus solitarius preproglucagon neurons. GIPR antagonism and Gipr\n                    <jats:sup>hypo-KO<\/jats:sup>\n                    also sensitise to cagrilintide-induced weight loss. Overall, our results suggest that the AP is responsible for the appetite-suppressing effects of GIPR agonism but that GIP receptors in the hypothalamus underlie the ability of GIPR antagonism to enhance the weight loss effects of GLP-1R and amylin receptor agonists.\n                  <\/jats:p>","DOI":"10.1038\/s42255-026-01575-z","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T09:02:35Z","timestamp":1784883755000},"page":"1669-1678","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Distinct brain regions mediate regulation of food intake in response to GIPR agonism or antagonism"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5722-6778","authenticated-orcid":false,"given":"Jo Edward","family":"Lewis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4232-482X","authenticated-orcid":false,"given":"Mireia","family":"Montaner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danae","family":"Nuzzaci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula-Peace","family":"James-Okoro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Harada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuya","family":"Inagaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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The Gribble-Reimann laboratory currently hosts projects that receive funding from AstraZeneca and has previously received funding from Eli Lilly and Company. F.M.G. and F.R. received sponsorship to host the European Incretin Study Group meeting (2024) from AstraZeneca, Eli Lilly, Mercodia and Sun Pharma. J.D.D., P.J.K. and W.S.D. are cofounders and shareholders in Volari Therapeutics. J.D.D. and P.J.K. receive research funding from Eli Lilly and Company that is unrelated to this work. The other authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}