The Dual Receptor Agonist Mechanism of Tizepatide Obesity Treatment

By Cocer Peptides      13 days ago

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Obesity is becoming an increasingly serious global issue, affecting not only physical health but also closely linked to chronic diseases such as cardiovascular disease and type 2 diabetes. Finding safe and effective weight loss methods has been a key focus of medical research. Tizepatide is a drug that acts on dual receptors, offering a new approach to obesity treatment.

Figure 1: Structure and initial steps of molecular signaling through GIPR and GLP1R in GIPR–GLP1R dual agonists RG7697–NNCOO90-2746 and LY3298176.

Tizepatide's Dual Receptor Agonist Mechanism

(1) GIP Receptor Agonist Mechanism

Physiological Basis of the GIP Receptor

The GIP receptor is a specialized cell receptor found in multiple organs, including the pancreas, adipose tissue, liver, and muscles. On the surface of pancreatic islet β cells, when the GIP hormone binds to this receptor, it activates intracellular signaling pathways, leading to an increase in intracellular cAMP levels. cAMP then activates protein kinase A, which, through a series of reactions, promotes insulin secretion.

In adipose tissue, activation of the GIP receptor regulates adipocyte metabolism. It promotes glucose uptake by adipocytes, increases fatty acid synthesis and storage, and inhibits lipolysis. Research suggests this process may be associated with an increase in the number of glucose transporters (GLUT4), which facilitate glucose entry into adipocytes, providing raw materials for fat synthesis.

The Effects of Tizepatide on the GIP Receptor

Tizepatide has a structure similar to the GIP hormone and can specifically bind to and activate GIP receptors. Compared to endogenous GIP, Tizepatide has a stronger binding affinity for receptors, enabling more effective activation of signaling pathways. Research has shown that after binding to receptors, it can sustainably increase cAMP levels, thereby more significantly promoting insulin secretion. In adipose tissue, its precise regulation of lipid metabolism after receptor activation enables both glucose uptake by adipocytes and balanced synthesis and storage of fatty acids, preventing excessive fat accumulation—a critical factor in maintaining normal lipid metabolism.

Figure 2: Comparative effects of RG7697/NNCOO90-2746 and LY3298176 from clinical trials, except where asterisks indicate (demonstrated only in rodents).

(2) GLP-1 Receptor Activation Mechanism

Physiological Basis of GLP-1 Receptors

The GLP-1 receptor is also a cell receptor primarily distributed in pancreatic β cells, the gastrointestinal tract, and the brain. In pancreatic β cells, GLP-1 binds to the receptor and activates signaling pathways to promote insulin secretion. Unlike GIP, the effects of GLP-1 are regulated by blood glucose levels: it promotes insulin secretion when blood glucose is high and its effects weaken when blood glucose is normal, making it safer.

In the gastrointestinal tract, activation of the GLP-1 receptor prolongs food retention in the stomach, preventing rapid postprandial blood glucose spikes, and also inhibits gastric acid secretion, protecting the gastrointestinal mucosa. In the brain, it acts on regions controlling appetite, reducing hunger and increasing satiety, thereby leading to reduced food intake.

Tizepatide's effects on the GLP-1 receptor

Tizepatide has a strong binding affinity for GLP-1 receptors, and upon activation, it produces effects similar to those of endogenous GLP-1. In terms of blood glucose regulation, it promotes insulin secretion based on blood glucose levels, thereby better controlling blood glucose. In the gastrointestinal tract, its effect of delaying gastric emptying is more pronounced than that of some traditional drugs. In the brain, its appetite-suppressing effect is more sustained, effectively aiding weight loss.

(3) Synergistic Effects of Dual Receptor Agonism

Synergistic Effects in Blood Glucose Regulation

Tizepatide acts on both GIP and GLP-1 receptors, resulting in better blood glucose regulation. GIP primarily rapidly promotes insulin secretion in the early postprandial period, reducing blood glucose peaks; GLP-1 continues to act throughout the postprandial process, not only promoting insulin secretion but also delaying gastric emptying, reducing food intake, and maintaining stable blood glucose levels. Activating both receptors simultaneously results in more optimal postprandial blood glucose control. For example, in diabetic animal experiments, Tizepatide reduced the postprandial blood glucose increase more than either GIP or GLP-1 drugs alone, and blood glucose returned to normal faster.

Synergistic Effects on Energy Metabolism

In terms of energy metabolism, GIP receptor agonists promote glucose uptake by fat cells, but under the influence of Tizepatide, fat synthesis does not accumulate excessively. Meanwhile, GLP-1 receptor agonists suppress appetite, increase satiety, reduce calorie intake, and promote fat burning and energy expenditure. This dual action balances energy intake and expenditure. For example, in obesity animal experiments, after using Tizepatide for a period of time, the animals' body weight decreased, body fat reduced, and basal metabolism accelerated.

Figure 3: Differences between synergistic agonists (chimeras) and peptide fusion structures

Application of Tizepatide in Obesity Treatment

(1) Weight Loss Effects

Preclinical Research Evidence

In animal experiments, obese mice administered Tizepatide showed gradual weight loss over time, with a more pronounced reduction compared to the control group. Analysis of body fat revealed that it not only reduced fat mass but also improved fat distribution, reducing visceral fat accumulation. The primary mechanisms are twofold: first, activation of the GLP-1 receptor suppresses appetite by inhibiting the brain's hunger center; second, it promotes fat burning and increases energy expenditure.

Clinical trial evidence

In clinical trials targeting obese patients, Tizepatide also demonstrated good weight loss effects. Multiple randomized controlled trials showed that after a period of treatment, patients' body weight decreased significantly. For example, in a 24-week trial, the treatment group experienced an average weight loss of approximately 10%, while the placebo group showed little change. Additionally, patients' waist circumference and hip circumference also decreased, indicating that it not only promotes weight loss but also improves fat distribution and reduces the risk of obesity-related diseases.

(2) Improvement of Metabolic Syndrome-Related Indicators

Improved Blood Glucose Regulation

Obesity patients often have blood glucose issues, and Tizepatide improves blood glucose control while promoting weight loss. In clinical trials, patients experienced significant reductions in fasting blood glucose, postprandial blood glucose, and hemoglobin A1c (a long-term blood glucose control indicator) after treatment. This is because it acts through dual receptor mechanisms, promoting insulin secretion and enhancing insulin sensitivity, while also delaying gastric emptying and reducing rapid food absorption. Compared to traditional antidiabetic medications, it not only lowers blood glucose but also promotes weight loss, offering greater benefits for obese patients with diabetes.

Lipid Regulation Improvement

Obesity is often accompanied by dyslipidemia, such as elevated triglycerides and low high-density lipoprotein (HDL) levels. Tizepatide can regulate lipids: after administration, patients experienced reduced triglyceride levels and increased HDL levels. This may be related to its regulation of lipid metabolism, such as promoting glucose uptake by fat cells, reducing fatty acid release, and enhancing fat oxidation, thereby improving lipid profiles and lowering cardiovascular disease risk.

(3) Potential benefits for the cardiovascular system

Blood pressure regulation

Obesity is one of the risk factors for hypertension. Clinical studies have found that after treatment with Tizepatide, patients' systolic and diastolic blood pressure both decrease. This may be related to weight loss and improved metabolism: weight loss reduces the burden on the heart, and improved blood glucose and lipid levels help restore vascular health and reduce vascular resistance. Additionally, its effects on the gastrointestinal tract may indirectly influence neuroendocrine regulation, thereby regulating blood pressure.

Vascular protective effects

Chronic inflammation and oxidative stress are common in obese patients, which can damage vascular endothelium and promote atherosclerosis. Tizepatide protects vascular endothelium by improving metabolism, reducing the release of inflammatory factors, and lowering oxidative stress. Studies show that after treatment, patients' inflammatory markers such as C-reactive protein (CRP) decreased, and vascular endothelial function indicators such as nitric oxide release increased, indicating improved vascular health and aiding in the prevention of cardiovascular diseases.

Conclusion

Tizepatide demonstrates significant potential in obesity treatment by simultaneously acting on GIP and GLP-1 receptors. It not only effectively promotes weight loss but also improves metabolic indicators such as blood glucose and lipid levels, while providing cardiovascular protection. Through its multifaceted mechanisms of action, it offers a new treatment option for obesity and related conditions.

Sources

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[2] Jensen T L, Nden A B O, Karstoft K, et al. Tirzepatide. Dual GLP-1/GIP receptor agonist, Treatment of type 2 diabetes and obesity[J]. Drugs of the Future, 2023. DOI:10.3389/fendo.2022.1004044

[3] Willard F S, Douros J D, Gabe M B, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist[J]. Jci Insight, 2020,5(17).DOI:10.1172/jci.insight.140532.

[4] Bastin M, Andreelli F. Dual GIP-GLP1-Receptor Agonists In The Treatment Of Type 2 Diabetes: A Short  Review On Emerging Data And Therapeutic Potential[J]. Diabetes Metabolic Syndrome and Obesity-Targets and Therapy, 2019,12:1973-1985.DOI:10.2147/DMSO.S191438.

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