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The study identifies a leptin-sensitizing mechanism mediated by tirzepatide (TZP), a dual-agonist targeting GLP-1R and GIPR. Clinical results show baseline circulating leptin levels correlate with weight-loss efficacy in obesity patients, indicating functional interaction. In diet-induced obesity mice, TZP plus leptin produces synergistic weight loss, improved hepatic insulin sensitivity, enhanced brown-fat thermogenesis, reduced food intake, increased energy expenditure, and strengthened hypothalamic leptin signaling.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/tirzepatide-synergizes-with-leptin-on-weight-loss-and-restoring-metabolic-homeostasis-in-diet-induced-obesity-model/451245/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/tirzepatide-synergizes-with-leptin-on-weight-loss-and-restoring-metabolic-homeostasis-in-diet-induced-obesity-model/451245.png","ImageObject",300,407,{"name":92,"@type":93},"Cipher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What problem does the study address regarding obesity treatment?","Question",{"text":113,"@type":114},"Leptin resistance limits the anti-obesity efficacy of leptin-based signaling, reducing sustained weight-loss benefits.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does tirzepatide relate to leptin in this work?",{"text":118,"@type":114},"Tirzepatide is proposed to sensitize leptin mechanisms, and baseline leptin levels in clinical trial participants correlate with weight-loss efficacy.",{"name":120,"@type":111,"acceptedAnswer":121},"What do the diet-induced obesity (DIO) mouse experiments show?",{"text":122,"@type":114},"Combining tirzepatide and leptin synergistically improves weight loss, hepatic insulin sensitivity, brown adipose thermogenic gene expression, and whole-body metabolic outcomes under thermoneutrality.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},451245,1791310270,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},687208528416,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","bioRxiv preprint doi: https://doi.org/10.64898/2025.12.18.695152; this version posted December 23 , 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \n1 Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic  \n2 Homeostasis in Diet-induced Obesity Model  \n3 Xun Sun 1,2,3, Yuexi Yin3, Min Song4, Brian A Droz4, Yanzhu Lin4, Kristen N. Beaty2, Baohua  \n4 Zhou 1, Hyun Cheol Roh2, Jonathan M. Wilson4, Paul F. Cain4, Ricardo J. Samms4, Patrick L.  \n5 Sheets3, Minrong Ai4†*, Hongxia Ren 1,2,3,5†‡*  \n6 1Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University  \n7 School of Medicine; Indianapolis, IN, USA.  \n8 2Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine;  \n9 Indianapolis, IN, USA.  \n10 3 Stark Neurosciences Research Institute, Indiana University School of Medicine; Indianapolis,  \n11 IN, USA.  \n12 4Lilly Research Laboratories, Eli Lilly and Company; Indianapolis, IN, USA.  \n13 5Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine;  \n14 Indianapolis, IN, USA.  \n15 †These authors contributed equally.  \n16 ‡Lead contact.  \n17 Running title: Synergistic effects oftirzepatide and leptin  \n18 *Corresponding authors:  \n19 Hongxia Ren  \n20 E-mail: [renh@iu.edu](renh@iu.edu)  \n[21](21 Phone: 317-274-1567)[ Phone: 317-274-1567](21 Phone: 317-274-1567)  \nbioRxiv preprint doi: [https://doi.org/10.64898/2025.12.18.695152](https://doi.org/10.64898/2025.12.18.695152); this version posted December 23, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \n22 Postal address: 1210 Waterway Blvd., Ste. 4100, Indianapolis, IN 46202, USA  \n23 Minrong Ai  \n24 E-mail: [ai_minrong@lilly.com](ai_minrong@lilly.com)  \n[25](25 Phone: 317-651-8497)[ Phone: 317-651-8497](25 Phone: 317-651-8497)  \n26 Postal address: 307 East Merrill St., Indianapolis, IN 46225 27  \n28  \n29  \n30  \n31  \n32  \n33  \n34  \n35  \n36  \n37  \n38  \nbioRxiv preprint doi: [https://doi.org/10.64898/2025.12.18.695152](https://doi.org/10.64898/2025.12.18.695152); this version posted December 23, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made  \navailable under aCC-BY-NC-ND 4.0 International license.  \n39 Abstract: Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing  \n40 mechanism through tirzepatide (TZP), a glucagon-like peptide-1 receptor (GLP-1R) and glucose- 41 dependent insulinotropic polypeptide receptor (GIPR) dual-agonist. Our tirzepatide clinical trial  \n42 revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients  \n43 with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on  \n44 weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the  \n45 synergistic effects oftirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep  \n46 treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene  \n47 expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed  \n48 TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide  \n49 sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R  \n50 expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the  \n51 inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a  \n52 ","cbCaikgMyMyt1GEe","https://ap.wps.com/l/cbCaikgMyMyt1GEe","pdf",4113014,43,"English","# Abstract\n# Introduction\n# Highlights\n# Abstract Background and Rationale\n# Mechanistic Findings (Leptin Signaling and Neuronal Activity)","[{\"question\":\"What problem does the study address regarding obesity treatment?\",\"answer\":\"Leptin resistance limits the anti-obesity efficacy of leptin-based signaling, reducing sustained weight-loss benefits.\"},{\"question\":\"How does tirzepatide relate to leptin in this work?\",\"answer\":\"Tirzepatide is proposed to sensitize leptin mechanisms, and baseline leptin levels in clinical trial participants correlate with weight-loss efficacy.\"},{\"question\":\"What do the diet-induced obesity (DIO) mouse experiments show?\",\"answer\":\"Combining tirzepatide and leptin synergistically improves weight loss, hepatic insulin sensitivity, brown adipose thermogenic gene expression, and whole-body metabolic outcomes under thermoneutrality.\"}]","Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic Homeostasis in Diet-induced Obesity Model | PDF",1790734658,108]