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Here, seeking to further improve the metabolic efficacy of GLP-1R\u2013GIPR co-agonism, we report the development of a unimolecular quintuple agonist\u00a0that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R\u2013GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via\u00a0its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1\u2013GIP\u2013lanifibranor is indistinguishable from GLP-1\u2013GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1\u2013GIP\u2013lanifibranor outperforms GLP-1R\u2013GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1\u2013GIP\u2013lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPAR\u03b4 and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1\u2013GIP\u2013lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10427-5","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T15:02:03Z","timestamp":1777474923000},"page":"776-785","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["GLP-1R\u2013GIPR\u2013PPAR\u03b1\/\u03b3\/\u03b4 quintuple agonism corrects obesity and diabetes in mice"],"prefix":"10.1038","volume":"653","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5859-6316","authenticated-orcid":false,"given":"Daniela","family":"Liskiewicz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Novikoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2204-8636","authenticated-orcid":false,"given":"Ahmed","family":"Khalil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seun","family":"Akindehin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4358-6331","authenticated-orcid":false,"given":"Jonathan E.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietra","family":"Candela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7446-6299","authenticated-orcid":false,"given":"Russell L.","family":"Castelino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Callum","family":"Coupland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7452-0867","authenticated-orcid":false,"given":"Maxime","family":"Culot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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(2016) and Bayer Pharma AG Berlin (2016). As former director of the Helmholtz Diabetes Center and the Institute for Diabetes and Obesity at Helmholtz Zentrum M\u00fcnchen (2011\u20132018), and since 2018, as CEO of Helmholtz Zentrum M\u00fcnchen, M.H.T. has been responsible for collaborations with a multitude of companies and institutions worldwide. In this capacity, M.H.T. discussed potential projects with and has signed\/signs contracts for his institute(s) and for the staff for research funding and\/or collaborations with industry and academia worldwide, including but not limited to pharmaceutical corporations such as Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medigene, Arbormed, BioSyngen and others. In this role, M.H.T. was\/is further responsible for commercial technology transfer activities of the institute(s), including diabetes related patent portfolios of Helmholtz Zentrum M\u00fcnchen such as WO\/2016\/188932 A2 or WO\/2017\/194499 A1. M.H.T. confirms that to the best of his knowledge none of the above funding sources were involved in the preparation of this paper. T.D.M. holds stock from Eli Lilly and receives research funding from Novo Nordisk. T.D.M. has further received speaking fees from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Merck, AstraZeneca and Mercodia. J.E.C. received funding from Novo Nordisk, Eli Lilly, Merck, Structure Therapeutics and Prostasis. J.E.C. has served as an advisor\/consultant in the past 12 months to Arrowhead Therapeutics, Boehringer Ingelheim, Neurocrine Biosciences, Prostasis, Protagonist and Structure Therapeutics. R.D.D. is a co-inventor on intellectual property owned by Indiana University and licensed to Novo Nordisk. R.D.D., B.F., J.D.D., S.A.M. and P.J.K. were previously employed by Novo Nordisk. J.D.D., S.A.M. and P.J.K. receive research funding from Eli Lilly and are co-founders and shareholders in Volari Therapeutics, both unrelated to this work. P.T.P. received speaker honoraria from Novo Nordisk. B.F. is a current employee of Eli Lilly. R.J.S. has received research support from Novo Nordisk, Fractyl, AstraZeneca, Congruence Therapeutics, Eli Lilly, Bullfrog AI, Glyscend Therapeutics and Amgen. R.J.S. has served as a paid consultant for Novo Nordisk, Eli Lilly, CinRx, Fractyl, Structure Therapeutics, Crinetics, Amgen, Congruence Therapeutics and Nuanced Health. R.J.S. has equity in Nuanced Health, Coro Bio. Fractyl and Rewind. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}