Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic Homeostasis in Diet-induced Obesity Model

Sep 30, 2026

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Leptin resistance limits anti-obesity efficacy. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages43

Reading Time1 h 48 min

AccessFree to download

Abstract

Introduction

Highlights

Abstract Background and Rationale

Mechanistic Findings (Leptin Signaling and Neuronal Activity)

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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.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 available under aCC-BY-NC-ND 4.0 International license. 1 Tirzepatide Synergizes with Leptin on Weight Loss and Restoring Metabolic 2 Homeostasis in Diet-induced Obesity Model 3 Xun Sun 1,2,3, Yuexi Yin3, Min Song4, Brian A Droz4, Yanzhu Lin4, Kristen N. Beaty2, Baohua 4 Zhou 1, Hyun Cheol Roh2, Jonathan M. Wilson4, Paul F. Cain4, Ricardo J. Samms4, Patrick L. 5 Sheets3, Minrong Ai4†*, Hongxia Ren 1,2,3,5†‡* 6 1Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University 7 School of Medicine; Indianapolis, IN, USA. 8 2Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine; 9 Indianapolis, IN, USA. 10 3 Stark Neurosciences Research Institute, Indiana University School of Medicine; Indianapolis, 11 IN, USA. 12 4Lilly Research Laboratories, Eli Lilly and Company; Indianapolis, IN, USA. 13 5Department of Anatomy, Cell Biology & Physiology, Indiana University School of Medicine; 14 Indianapolis, IN, USA. 15 †These authors contributed equally. 16 ‡Lead contact. 17 Running title: Synergistic effects oftirzepatide and leptin 18 *Corresponding authors: 19 Hongxia Ren 20 E-mail: [renh@iu.edu](renh@iu.edu) [21](21 Phone: 317-274-1567)[ Phone: 317-274-1567](21 Phone: 317-274-1567) bioRxiv 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 available under aCC-BY-NC-ND 4.0 International license. 22 Postal address: 1210 Waterway Blvd., Ste. 4100, Indianapolis, IN 46202, USA 23 Minrong Ai 24 E-mail: [ai_minrong@lilly.com](ai_minrong@lilly.com) [25](25 Phone: 317-651-8497)[ Phone: 317-651-8497](25 Phone: 317-651-8497) 26 Postal address: 307 East Merrill St., Indianapolis, IN 46225 27 28 29 30 31 32 33 34 35 36 37 38 bioRxiv 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 available under aCC-BY-NC-ND 4.0 International license. 39 Abstract: Leptin resistance limits anti-obesity efficacy. We identified a leptin-sensitizing 40 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 42 revealed that circulating leptin levels at baseline correlated with weight loss efficacy in patients 43 with obesity, suggesting leptin and tirzepatide could interact to achieve stronger effects on 44 weight loss. Next, we utilized the diet-induced obesity (DIO) mice and demonstrated the 45 synergistic effects oftirzepatide and leptin combination (TZP+Lep) on weight loss. TZP+Lep 46 treatment further improved hepatic insulin sensitivity and upregulated thermogenetic gene 47 expression in brown adipose tissue. Metabolic profiling under thermoneutrality revealed 48 TZP+Lep treatment further reduced food intake and increased energy expenditure. Tirzepatide 49 sensitized leptin signaling in hypothalamic pro-opiomelanocortin (POMC) and GLP-1R 50 expressing neurons. TZP+Lep synergistically increased POMC neuronal firing by decreasing the 51 inhibitory postsynaptic input. Together, our work showed combining tirzepatide and leptin as a 52

FAQs

What problem does the study address regarding obesity treatment?

Leptin resistance limits the anti-obesity efficacy of leptin-based signaling, reducing sustained weight-loss benefits.

How does tirzepatide relate to leptin in this work?

Tirzepatide is proposed to sensitize leptin mechanisms, and baseline leptin levels in clinical trial participants correlate with weight-loss efficacy.

What do the diet-induced obesity (DIO) mouse experiments show?

Combining tirzepatide and leptin synergistically improves weight loss, hepatic insulin sensitivity, brown adipose thermogenic gene expression, and whole-body metabolic outcomes under thermoneutrality.

Sep 30, 2026

Uploaded by Cipher