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We then compared the effects of short\u2010term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco\u2010behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti\u2010related protein (AgRP)\u2010Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Semaglutide reduced food intake by amplifying the feeding\u2010inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.14663","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T05:15:46Z","timestamp":1644210946000},"page":"1010-1020","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Growth differentiation factor 15 (\n                    <scp>GDF15<\/scp>\n                    ) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms"],"prefix":"10.1111","volume":"24","author":[{"given":"M.","family":"Ghidewon","sequence":"first","affiliation":[{"name":"Institute of Diabetes, Obesity and Metabolism and School of Arts and Sciences University of Pennsylvania  Philadelphia Pennsylvania"},{"name":"Department of Neuroscience University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.S.","family":"Wald","sequence":"additional","affiliation":[{"name":"Institute of Diabetes, Obesity and Metabolism and School of Arts and Sciences University of Pennsylvania  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. D.","family":"McKnight","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Pennsylvania  Philadelphia Pennsylvania"},{"name":"Monell Chemical Senses Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-5355","authenticated-orcid":false,"given":"B. C.","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania  Philadelphia Pennsylvania"},{"name":"Department of Psychiatry University of Pennsylvania, Perelman School of Medicine  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. M.","family":"Breen","sequence":"additional","affiliation":[{"name":"Internal Medicine Research Unit Pfizer Global R&amp;D  Cambridge Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. L.","family":"Alhadeff","sequence":"additional","affiliation":[{"name":"Department of Neuroscience University of Pennsylvania  Philadelphia Pennsylvania"},{"name":"Monell Chemical Senses Center  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9438-695X","authenticated-orcid":false,"given":"T.","family":"Borner","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Sciences School of Nursing, University of Pennsylvania  Philadelphia Pennsylvania"},{"name":"Department of Psychiatry University of Pennsylvania, Perelman School of Medicine  Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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