2. Academic Validation
  3. Tirzepatide retention in iWAT with mesoporous polydopamine encapsulation enhances weight loss through leptin receptor signaling

Tirzepatide retention in iWAT with mesoporous polydopamine encapsulation enhances weight loss through leptin receptor signaling

  • J Adv Res. 2025 Sep 11:S2090-1232(25)00692-7. doi: 10.1016/j.jare.2025.09.009.
Lin Mi 1,  Tan Li 2,  Xiaoxin Xiang 3,  Yimin Zhou 3,  Na Xiong 3,  Yanyu Chen 4,  Jiaoting Chen 5,  Sijia Shang 5,  Shumeng Chen 3,  Wai W Cheung 6,  Zecong Xiao 7,  Yanming Chen 3,  Jiahai Wang 8,  Jun Peng 9,  Xintao Shuai 10,  Guojun Shi 11
Affiliations

Affiliations

  • 1 Department of Endocrinology and Metabolism, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Yunkang School of Medicine and Health, Nanfang College of Guangzhou, Guangzhou, Guangdong, China.
  • 2 The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
  • 3 Department of Endocrinology and Metabolism, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 4 Department of Endocrinology and Metabolism, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Hematology, Institute of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 5 Department of Hematology & Biomedical Innovation Center, The Six Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 6 Department of Pediatrics, University of California, San Diego, CA, United States.
  • 7 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 8 School of Chemistry and Chemical Engineering, Guangzhou University, Guangzhou, Guangdong, China.
  • 9 Department of Endocrinology and Metabolism, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address: pengj266@mail.sysu.edu.cn.
  • 10 Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address: shuaixt@mail.sysu.edu.cn.
  • 11 Department of Endocrinology and Metabolism, Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Nanomedicine Research Center, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address: shigj6@mail.sysu.edu.cn.
PMID: 40945849 DOI: 10.1016/j.jare.2025.09.009
Abstract

Introduction: Tirzepatide (TZP), a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor agonist, has been showing superior benefits in weight loss and glucose lowering in patients with obesity, while the tissue-specific mechanisms of TZP as well as its side effects remain to be investigated.

Objectives: We aimed to explore whether localized injection of TZP into inguinal white adipose tissue (iWAT) would be as effective as subcutaneous injection for weight loss, in order to understand the local effects and signaling pathways of TZP for precision medicine.

Methods: Mesoporous polydopamine was synthesized and mixed with TZP for encapsulation (MPDA@TZP), followed by characterization of its retention in iWAT after local injection. Both diet-induced obesity (DIO) mice and db/db mice received local injection of TZP, and transcriptomic analysis of iWATs was performed. iWATs were also dissected for ex vivo assays.

Results: MPDA@TZP successfully increased the retention time of TZP in the iWAT of mice and had a more dramatic effect on weight loss and improvement in plasma lipid profiles compared to TZP alone in DIO mice, while showing comparable glucose-lowering efficacy. Transcriptomic analysis indicated that iWAT injection of MPDA@TZP improved Leptin resistance, beiging, lipid metabolism, mitochondrial activity and branched-chain amino acid (BCAA) catabolism in iWAT. Leptin receptor deficiency in db/db mice abolished the weight reduction effect of MPDA@TZP via iWAT local injection compared to that in DIO mice, while the glucose-lowering effects were comparable in both db/db and DIO mice.

Conclusion: These findings indicate that the retention of TZP in iWAT via MPDA encapsulation amplified its effect on weight loss in mice through Leptin receptor signaling compared with TZP alone, which provides new insights into the tissue-specific mechanism and alternative delivery strategies of TZP for targeting specific WAT tissues.

Keywords

Leptin receptor signaling; MPDA; Obesity; Tirzepatide; inguinal WAT.

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