Study Reveals Tirzepatide Regulates Adipocyte Nutritional Metabolism Through Long-Acting Activation of GIP Receptor

Academic Background

With global chronic nutritional excess and lack of exercise, obesity and type 2 diabetes (T2D) and their related complications (such as cardiovascular diseases) have reached epidemic levels. These conditions not only affect people’s daily lives but also increase the burden on healthcare systems. While lifestyle changes and therapeutic interventions are effective in controlling blood sugar and maintaining weight, they are often difficult to sustain in the long term. New treatments urgently need to be developed to address these unmet medical needs. Tirzepatide is a novel long-acting glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) agonist. Clinical trials have shown that it has better efficacy in lowering HbA1c, weight, and serum triglyceride levels compared to placebo or selective GLP-1R agonists. However, the mechanism of how GIPR and GLP-1R co-activation improves clinical outcomes has not been fully elucidated.

Study Origin

This paper was authored by researchers Ajit Regmi, Eitaro Aihara, Michael E. Christe, and others from Eli Lilly and Company, in collaboration with researchers from Leiden University Medical Center in the Netherlands. The paper was published in the journal “Cell Metabolism” on July 2, 2024, DOI: https://doi.org/10.1016/j.cmet.2024.05.010.

Study Content

Research Process

1. Experimental Design and Tool Development: The research team developed fluorescein-labeled Tirzepatide (TZP-FL), a selective GIPR agonist (GIPRA-FL), and a selective GLP-1R agonist (EX4-FL) for imaging in vitro and in vivo experiments.

2. Adipose Tissue Processing: Through processing of whole adipose tissue, researchers observed the binding of TZP-FL to the membranes of human and mouse adipocytes as well as blood vessels, indicating that Tirzepatide binds adipocytes through GIPR.

3. Gene Expression Analysis: Using RT-PCR and RNA mixture probes, the expression of GIPR and GLP-1R genes in cells isolated from adipocytes and stromal vascular fraction (SVF) was detected, and GIPR functional activity in adipocytes was verified through cAMP accumulation and lipolysis assays.

4. Functional Measurement: The study investigated the effects of Tirzepatide and GIP on glucose and lipid metabolism in differentiated human adipocytes, both in the presence and absence of insulin.

Main Research Results

1. Expression and Signal Transduction of GIPR in Adipocytes: The experiments showed that most adipocytes in human and mouse adipose tissue express GIPR, while GLP-1R is not expressed in adipocytes. Tirzepatide and GIPR agonists can enhance insulin signaling, glucose uptake, and lipolysis, whereas GLP-1R agonists do not have these effects.

2. Metabolic Regulation Via GIPR Signaling Activation: In adipocytes, Tirzepatide and GIP can synergistically enhance glucose uptake and conversion into glycerol with insulin; without insulin, GIPR agonist can enhance lipolysis.

3. Long-term Metabolic Effects of GIPR Activation: In a high-fat diet-induced obese mouse model, long-term GIPR agonist treatment can reduce triglyceride levels in the blood and promote uptake of lipoprotein-derived fatty acids by adipose tissue.

4. Analysis of Metabolic Pathways: Transcriptome analysis revealed the roles of Tirzepatide and GIP in various metabolic pathways, including enhancing the tricarboxylic acid (TCA) cycle and inhibiting triglyceride biosynthesis, actions independent of insulin.

Conclusion and Significance

Through dual long-acting activation of GIPR and GLP-1R, Tirzepatide shows significant advantages in reducing blood sugar, weight, and triglyceride levels. These effects are achieved not only through enhanced insulin secretion and action but also by directly regulating the metabolic functions of adipocytes. Long-term GIPR agonism can enhance fat release in fasting states and promote lipid and glucose storage in feeding states, ultimately improving overall metabolic balance. This provides new insights into the complex mechanisms of GIPR and GLP-1R co-activation.

Research Highlights

1. Novel Drug Mechanism: For the first time, the study reveals the specific mechanism by which Tirzepatide directly regulates adipocyte metabolism through long-acting activation of GIPR.
2. Molecular-Level Analysis: Analyzed the effect of Tirzepatide on key regulatory factors and gene expression in metabolic pathways within adipocytes in both the presence and absence of insulin.
3. Potential Clinical Application: Provides a mechanistic basis for the significant improvement of blood sugar, weight, and lipids in T2D patients clinically observed with Tirzepatide.

Other Valuable Information

The study also found that Tirzepatide enhances lipid clearance and storage, potentially helping to reduce serum triglycerides and improve overall lipid metabolism distribution, thereby reducing ectopic fat accumulation and enhancing insulin sensitivity. This research provides important theoretical support for the design of novel GIPR and GLP-1R co-agonists and lays the foundation for their future clinical application. Further clinical research is needed to verify these findings and explore their applications in different patient populations.

This study not only reveals the molecular mechanism of Tirzepatide in regulating adipocyte function through long-acting GIPR activation but also provides scientific evidence for its clinical improvement in overall metabolic health in T2D patients.