The Peptide That Suppresses Appetite Three Ways

What Retatrutide Is

Retatrutide is a next-generation weight-loss and metabolic peptide that simultaneously activates three key hormone receptors: GLP-1, GIP, and glucagon. It’s not a mixture of three separate peptides, but one engineered peptide that mimics the actions of all three natural hormones at once, giving it a powerful, multi-pathway effect on appetite, blood sugar, and fat metabolism (1).

The “Three Peptides” in Retatrutide

Retatrutide is a single synthetic peptide designed to act as a triple agonist at three receptors (1):

• GLP-1 receptor (glucagon-like peptide-1 receptor)
• GIP receptor (glucose-dependent insulinotropic polypeptide receptor)
• Glucagon receptor (GCG receptor)

The three natural hormones whose receptors retatrutide activates are (1):

1. Glucagon-like peptide-1 (GLP-1)
2. Glucose-dependent insulinotropic polypeptide (GIP)
3. Glucagon (GCG)

Mechanism of Action

Retatrutide binds to and activates all three receptors, triggering a coordinated metabolic response (1,2).

On GLP-1 receptors, it:

• Slows gastric emptying, so food stays in the stomach longer.
• Increases insulin release in a glucose-dependent way (only when blood sugar is high).
• Suppresses glucagon, helping lower blood sugar.
• Acts on the brain (hypothalamus, brainstem) to reduce appetite and increase satiety.

On GIP receptors, it:

• Enhances insulin secretion from pancreatic beta cells.
• Promotes nutrient storage in fat and muscle, improving insulin sensitivity.
• In the brain, it may further support appetite control and energy balance.

On glucagon receptors, it:

• Stimulates the liver to increase energy expenditure (fat burning).
• Promotes lipolysis (fat breakdown) and ketone production.
• Helps mobilize stored fat, contributing to greater weight loss beyond calorie restriction alone (2).

Together, this triple action leads to:

• Strong appetite suppression and reduced food intake.
• Improved insulin sensitivity and glycemic control.
• Increased energy expenditure and fat oxidation.
• Significant weight loss (up to ~24% in phase 2 trials) and reduced liver fat (3,4).

Where These Hormones Are Produced

The three hormones that retatrutide mimics are all naturally produced in the body (4,5,6,7):

• GLP-1 (glucagon-like peptide-1): Made by L-cells in the small intestine (especially the ileum and colon) in response to food, with smaller amounts produced in the pancreas and brain.
• GIP (glucose-dependent insulinotropic polypeptide): Made by K-cells in the upper small intestine (duodenum and jejunum) after eating and released into the blood to act on the pancreas, fat, and other tissues.
• Glucagon: Primarily produced by alpha cells in the pancreas, with smaller amounts made in the small intestine and brain. Glucagon is released when blood sugar is low to stimulate glucose production in the liver.

Retatrutide vs Natural Hormones

How Retatrutide acts on the three receptors compared to natural endogenous hormones GLP-1, GIP, and glucagon (2,5,6,7):

• Natural GLP-1, GIP, and glucagon are broken down in minutes to hours.
• Retatrutide has a half-life of about 6 days, so it stays in the body for roughly 4–5 weeks after the last dose.

Comparing Retatrutide to Semaglutide and Tirzepatide

All are used for the management of type 2 diabetes and obesity. However, Retatrutide targets 3 receptors, compared to Tirzepatide, which targets 2 receptors, and Semaglutide, only 1.

• Semaglutide acts as a glucagon-like peptide-1 (GLP-1) receptor agonist, enhancing glucose-dependent insulin secretion, delaying gastric emptying, and reducing appetite (8).
• Tirzepatide functions as a dual agonist of the GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, promoting insulin release and improving glycemic control, with added weight-loss benefits (9).
• Retatrutide advances as a triple agonist targeting GLP-1, GIP, and glucagon receptors, yielding superior reductions in food intake, liver fat, and body weight in trials. It also targets glucagon receptors, giving it the advantage in weight loss.

References

1. Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide-A Game Changer in Obesity Pharmacotherapy. Biomolecules. 2025 May 30;15(6):796. doi: 10.3390/biom15060796. PMID: 40563436; PMCID: PMC12190491.
2. Coskun T, et al. Retatrutide (LY3437943), a triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, and glucagon receptors for the treatment of obesity: a phase 1 study. Lancet Diabetes Endocrinol. 2023;11(10):721–732. doi:10.1016/S2213-8587(23)00206-0.
3. Katsi V, Koutsopoulos G, Fragoulis C, Dimitriadis K, Tsioufis K. Retatrutide-A Game Changer in Obesity Pharmacotherapy. Biomolecules. 2025 May 30;15(6):796. doi: 10.3390/biom15060796. PMID: 40563436; PMCID: PMC12190491.
4. Cabou, C., & Burcelin, R. (2011). GLP-1, the gut-brain, and brain-periphery axes. The review of diabetic studies : RDS, 8(3), 418–431. https://doi.org/10.1900/RDS.2011.8.418
5. Meier, J. J., Nauck, M. A., Kranz, D., Holst, J. J., Deacon, C. F., Gaeckler, D., Schmidt, W. E., & Gallwitz, B. (2004). Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes, 53(3), 654–662. https://doi.org/10.2337/diabetes.53.3.654
6. Hjort, U. J., Christensen, M. B., & Holst, J. J. (2019). Glucagon physiology. In L. J. De Groot, G. Chrousos, K. Dungan, K. R. Feingold, A. Grossman, J. M. Hershman, C. Koch, R. J. Korbonits, R. McLachlan, M. New, J. Purnell, R. Rebar, F. Singer, D. L. Trence, A. Vinik, & D. P. Wilson (Eds.), Endotext. MDText.com, Inc. https://www.ncbi.nlm.nih.gov/books/NBK279127/
7. Naeem, M., Imran, L., & Banatwala, U. E. S. S. (2024). Unleashing the power of retatrutide: A possible triumph over obesity and overweight: A correspondence. Health science reports, 7(2), e1864. https://doi.org/10.1002/hsr2.1864
8. Papakonstantinou, I., Tsioufis, K., & Katsi, V. (2024). Spotlight on the Mechanism of Action of Semaglutide. Current issues in molecular biology, 46(12), 14514–14541. https://doi.org/10.3390/cimb46120872
9. Garvey WT, Batterham RL, Bhatta M, Buscemi S, Christensen LN, Frias JP, Jódar E, Kandler K, Rigas G, Wadden TA, Wharton S; STEP 5 Study Group. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med. 2022 Oct;28(10):2083-2091. doi: 10.1038/s41591-022-02026-4. Epub 2022 Oct 10. PMID: 36216945; PMCID: PMC9556320.
10. Vanderbilt University Medical Center. (2023, October 17). Tirzepatide trial shows additional 21.1% weight loss following intensive lifestyle intervention. https://news.vumc.org/2023/10/17/tirzepatide-trial-shows-additional-21-1-weight-loss-following-intensive-lifestyle-intervention/
11. Garvey, W. T., Batterham, R. L., Bhatta, M., Buscemi, S., Christensen, L. N., Frias, J. P., Jódar, E., Kandler, K., Lingvay, I., McGowan, B. M., O’Neil, P. M., Rubino, D. M., & Jensen, C. (2022). Two-year effects of semaglutide in adults with overweight or obesity: The STEP 5 trial. Nature Medicine, 28(10), 2083–2091. https://doi.org/10.1038/s41591-022-02026-4