{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:03:56Z","timestamp":1786122236631,"version":"build-2736575974"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T00:00:00Z","timestamp":1783296000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2022JJ40159"],"award-info":[{"award-number":["2022JJ40159"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32371327"],"award-info":[{"award-number":["32371327"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The GLP\u20101 receptor (GLP\u20101R) and GIP receptor (GIPR) are key targets for diabetes and obesity therapies. Pharmacological agents including GLP\u20101R agonists (e.g., Semaglutide), dual GLP\u20101R\/GIPR agonists (e.g., Tirzepatide) and a GLP\u20101R agonist\/GIPR antagonist (AMG133) have demonstrated considerable promise in anti\u2010diabetic and weight management applications. However, a systematic comparison of the specific contributions of GIPR activation versus GIPR inhibition to weight loss within the context of GLP\u20101\/GIP dual\u2010targeting therapies remains unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Research Design and Methods<\/jats:title>\n                    <jats:p>To address this, we designed three IgG4 Fc\u2010fusion proteins: a GLP\u20101R agonist\/GIPR agonist, (i) GLP\u20101(A8G)\/GIP(A2G)\u2010Fc; a GLP\u20101R agonist\/GIPR inhibitor, (ii) GLP\u20101(A8G)\/GIP(3\u201330)\u2010Fc; and a sequential molecule that hypothesised to transition from dual GLP\u20101R\/GIPR agonism to GLP\u20101R agonism\/GIPR inhibition, (iii) GLP\u20101(A8G)\/GIP(1\u201330)\u2010Fc. Mono\u2010agonist GLP\u20101(A8G)\u2010Fc and dual\u2010agonist GLP\u20101(A8G)\/GIP(A2G)\u2010Fc were used as controls to investigate the weight loss effects of GIPR activation and inhibition in DIO mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our findings revealed that the sequential molecule GLP\u20101(A8G)\/GIP(1\u201330)\u2010Fc produced the greatest body weight reduction (21.59%), significantly outperforming GLP\u20101(A8G)\/GIP(3\u201330)\u2010Fc (14.5%;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001). Furthermore, both GIPR activation and inhibition, when combined with GLP\u20101R agonism, markedly improved serum and hepatic lipid metabolism, as evidenced by reduced triglycerides and total cholesterol.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, these findings validate a peptide\u2010based inhibitory strategy for synergistic weight loss and provide insights into the differential metabolic roles of GIPR activation versus inhibition, guiding the development of novel anti\u2010obesity therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.70967","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T03:32:55Z","timestamp":1783395175000},"page":"8613-8626","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Sequential Dual\n                    <scp>GLP<\/scp>\n                    \u2010\n                    <scp>1R<\/scp>\n                    \/\n                    <scp>GIPR<\/scp>\n                    Agonist\u2010To\u2010Antagonist Molecule Achieves Superior Weight Loss in Obese Mice"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-0491-6769","authenticated-orcid":false,"given":"Yunxiao","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binhui","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guyu","family":"Zhong","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchen","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaofeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering Hunan University of Science and Engineering  Yongzhou Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezheng","family":"Peng","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry and Chemical Engineering Hunan Institute of Science and Technology  Yueyang Hunan China"},{"name":"Shenzhen Pengtai Biotechnology co., Ltd  Shenzhen Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,6]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0260158"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/35007508"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.12.068"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.101102"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468-1253(24)00188-2"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/13543784.2025.2472408"},{"key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"1973","DOI":"10.2147\/DMSO.S191438","article-title":"Dual GIP\u2010GLP1\u2010Receptor Agonists in the Treatment of Type 2 Diabetes: A Short Review on 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