A novel GIPR/GLP-1R dual agonist improves systemic metabolism through differentially regulating inflammation and lipid metabolism in obesity

  • J Adv Res. 2026 Feb 12:S2090-1232(26)00137-2. doi: 10.1016/j.jare.2026.02.006.
Feng Zhang  1 ,  Wei Chen  2 ,  Huiying Wang  2 ,  Dan Wu  2 ,  Zhinan Chen  2 ,  Ruitang Cheng  2 ,  Jinying Hu  2 ,  Lijun Xie  2 ,  Yan Qiu  3 ,  Zhiguang Zhou  2 ,  Tian Li  4 ,  Zhiqiang Du  5 ,  Fang Hu  6
Affiliations
  • 1. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China; Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Neurodegenerative Diseases, Changsha Medical University, Changsha, China.
  • 2. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
  • 3. Innovation Center, Tonghua Dongbao Pharmaceutical Co., Ltd, Longemont International Building, 1018 Changning Road, Changning District, 200042 Shanghai, China.
  • 4. Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China. Electronic address: [email protected].
  • 5. Innovation Center, Tonghua Dongbao Pharmaceutical Co., Ltd, Longemont International Building, 1018 Changning Road, Changning District, 200042 Shanghai, China. Electronic address: [email protected].
  • 6. National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China. Electronic address: [email protected].
PMID: 41690462 DOI: 10.1016/j.jare.2026.02.006
Abstract

Introduction: Dual GIP/GLP-1 Receptor agonists have gained significant attention in clinical applications because of their remarkable efficacy in reducing obesity and type 2 diabetes. However, the mechanisms by which these dual agonists affect systemic metabolism remain elusive.

Objectives: To investigate the effects of a novel dual-receptor agonist, THDBH120, on systemic metabolism in obese individuals and the specific roles of GIPR and GLP-1R in modulating systemic and adipose tissue metabolism.

Methods: To evaluate the intrinsic properties of THDBH120, we conducted a potency assay by using HEK293 cell lines overexpressing either human GIPR or GLP-1R and measured the accumulation of cAMP as a downstream second messenger following receptor activation. To evaluate the efficacy of THDBH120 on systemic metabolism, we used obese rodents and nonhuman primate species that received various doses and frequencies of THDBH120. To determine the metabolic roles of GLP-1R and GIPR in mediating the beneficial effects of THDBH120, we used GLP-1R- and GIPR-knockout mouse models treated with THDBH120, the GLP-1R agonist semaglutide, or the GIPR agonist LAGIPRA and performed transcriptomic Sequencing analyses of adipose tissues.

Results: THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has superior weight loss and metabolic improvement effects in rodents and mammals. The activation of GLP-1R by semaglutide or THDBH120 improved lipid metabolism, whereas the activation of GIPR by LAGIPRA or THDBH120 alleviated inflammation. THDBH120 improved lipid metabolism via GLP-1R-mediated pathways and mitigated inflammation by activating GIPR-associated pathways in the adipose tissues of obese mice.

Conclusion: Both GLP-1R and GIPR are important in mediating the beneficial effects of dual receptors on systemic metabolism. THDBH120 is a novel long-acting dual GIPR/GLP-1R agonist that has potential clinical applications.

Keywords
Adipose tissue; GIPR/GLP-1R dual agonist; Inflammation; Lipid metabolism; Obesity.
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