{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:46:55Z","timestamp":1787503615008,"version":"build-2736575974"},"posted":{"date-parts":[[2025,12,23]]},"group-title":"Neuroscience","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T00:00:00Z","timestamp":1766448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Lilly Research Laboratories","award":["Lilly Research Award Program"],"award-info":[{"award-number":["Lilly Research Award Program"]}]},{"name":"NIH NIDDK","award":["R01DK120772"],"award-info":[{"award-number":["R01DK120772"]}]},{"DOI":"10.13039\/100006108","name":"NIH NCATS","doi-asserted-by":"crossref","award":["R03TR003350"],"award-info":[{"award-number":["R03TR003350"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006108","name":"NIH NCATS","doi-asserted-by":"crossref","award":["UL1TR002529"],"award-info":[{"award-number":["UL1TR002529"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"crossref"}]},{"award":["Biomedical Research Grant"],"award-info":[{"award-number":["Biomedical Research Grant"]}],"id":[{"id":"https:\/\/ror.org\/02ets8c94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Bridge Award"],"award-info":[{"award-number":["Bridge Award"]}],"id":[{"id":"https:\/\/ror.org\/02ets8c94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["CTSI P&F core facility award"],"award-info":[{"award-number":["CTSI P&F core facility award"]}],"id":[{"id":"https:\/\/ror.org\/02ets8c94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the synergistic effects of tirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a potential way for better maintenance of metabolic homeostasis in obesity management.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Tirzepatide and leptin synergistically promote weight loss through reduced food intake and increased energy expenditure.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Tirzepatide and leptin synergistically improve insulin sensitivity and metabolic homeostasis with altered hepatic and adipose gene expression.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Tirzepatide sensitizes leptin signaling in hypothalamic GLP-1R and POMC neurons.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Tirzepatide and leptin synergistically increase POMC neuronal firing by decreasing inhibitory postsynaptic input.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.64898\/2025.12.18.695152","type":"posted-content","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T23:30:17Z","timestamp":1766532617000},"source":"Crossref","is-referenced-by-count":2,"title":["Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic Homeostasis in Diet-induced Obesity Model"],"prefix":"10.64898","author":[{"given":"Xun","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuexi","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A","family":"Droz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanzhu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen N.","family":"Beaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baohua","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-5747","authenticated-orcid":false,"given":"Hyun Cheol","family":"Roh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan M.","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Cain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo J.","family":"Samms","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L.","family":"Sheets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minrong","family":"Ai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2909-4365","authenticated-orcid":false,"given":"Hongxia","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122608250600000_2025.12.18.695152v1.1","doi-asserted-by":"crossref","unstructured":"C. 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