Retatrutide (8mg)


Size: 8mg
Contents: Retatrutide
Form: Lyophilized powder
Purity: >99%

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Retatrutide Peptide

Retatrutide, identified also by its code LY3437943, represents a synthetic peptide, which research indicates functions as a triple agonist. This compound comprises a 39-amino-acid sequence, engineered as an analog to the gastric inhibitory polypeptide (GIP), with additional affinity observed towards the glucagon-like peptide-1 (GLP-1) receptor and the glucagon (GCG) receptor.(1)(2) Typically, these receptors are engaged by their corresponding hormones GIP, GLP-1, and GCG, which appear to serve as critical hormonal regulators within the endocrine system. It is hypothesized that GLP-1 and GIP, as incretin hormones, may contribute to the stimulation of insulin secretion from pancreatic beta cells, and may enhance satiety following calorie intake. Conversely, glucagon is thought to play a compensatory role by potentially raising glucose levels during periods without food intake. It is also theorized that stimulation of GLP-1 receptors may decelerate gastric emptying. On the other hand, activation of GCG receptors might promote increased energy expenditure and fat tissue metabolism, particularly by influencing liver processes and converting white fat cells to beige fat cells. This is believed to possess thermogenic qualities akin to brown fat cells, possibly boosting thermogenesis and metabolic rates. The potential interaction of Retatrutide with these receptors suggests a complex impact on metabolic regulation that may be of interest in glycemic control and weight management research models. Furthermore, Retatrutide has been chemically modified with a C20 moiety, purportedly to extend its half-life to approximately six days.(3)

Chemical Makeup

Molecular Formula: C223H343F3N46O70
Molecular Weight: 4731.55 g/mol
Other Known Titles: LY3437943, NOP2Y096GV

Research and Clinical Studies

Retatrutide and Appetite

A phase 2 experiment, which lasted for 48 weeks, extended the hypothesis that Retatrutide may lead to a significant reduction in total energy consumption and help in the maintenance of a caloric deficit.(4) Retatrutide appeared to be associated with over 24.2% reduction in baseline weight, compared to 2.1% seen in the control model. The researchers also noted potential in indicators related to cholesterol metabolism, glucose, and insulin metabolism in the tested models. They commented that peptide exposure was associated with positive outcomes ”in cardiometabolic measures (exploratory endpoints) including systolic and diastolic blood pressure and levels of glycated hemoglobin, fasting glucose, insulin, and lipids.

Retatrutide and Glycated Hemoglobin

Retatrutide has been suggested to lower glycated hemoglobin (HbA1c) in models of hyperglycemia and baseline HbA1c over 7%. Phase 2 trials lasting up to 36 weeks posit that the peptide may lower glycated hemoglobin levels by up to 2.16% (23.59mmol/mol), which marks a potentially significant improvement of hyperglycemia.(5) The researchers also note that “bodyweight decreased significantly from baseline to 36 weeks in the Retatrutide groups (up to a least-squares mean of 16·94%).

Retatrutide and GIP receptors

One of the potential mechanisms of Retatrutide is the activation of the GIP receptors. A study delved into the nuanced roles that GIP receptor activation may potentially play in regulating energy balance. The researchers suggested that such an activation may be possible through the peptide’s potential within central neural pathways, particularly key brain regions such as the hypothalamus and brainstem.(6) These regions are considered critical for regulating energy homeostasis and appetite control. It is posited that GIP receptor agonists might directly engage neurons in these areas, potentially leading to altered neuronal activity that may result in decreased caloric intake and an overall negative energy balance. The hypothalamus, a central player in this mechanism, contains specific nuclei, such as the arcuate, paraventricular, and ventromedial nuclei, all deemed integral to appetite and energy expenditure regulation.

Activation of GIP receptors within these nuclei might suppress appetite or enhance satiety signals. For example, GIP receptor activation in the arcuate nucleus may influence neurons that produce neuropeptide Y (NPY), which is believed to increase appetite, and pro-opiomelanocortin (POMC), which appears to suppress appetite. This suggests that GIP receptor agonists may modulate these peptidergic systems, potentially leading to reduced food intake. Furthermore, the study also explores the potential of GIP receptor agonists to impact the brain’s emetic centers. By potentially modulating neural circuits in the area postrema and nucleus tractus solitarius of the brainstem, which are considered key sites for the initiation of nausea and vomiting responses, GIP receptor agonists might inhibit these responses. Additionally, the role of GIP receptor agonists in enhancing the permeability of the blood-brain barrier (BBB) may be a possible mechanism to improve the delivery and efficacy of agents targeting brain tissue regions involved in energy balance. This may involve the modulation of tight junctions or the transport systems within the neurovascular unit, allowing better access of these agents to the Central Nervous System (CNS).

Retatrutide and GLP-1 Receptors

Research has proposed that Retatrutide may exert potential via activating GLP-1 receptors distributed throughout the organism, potentially leading to a variety of outcomes. Specifically, this peptide might interact with GLP-1 receptors located in the pancreas, potentially stimulating the production of insulin by pancreatic beta cells and possibly reducing the production of glucagon by alpha cells in a glucose-sensitive manner. The GLP-1 receptor, classified within the B family of G protein-coupled receptors, primarily seems to engage the cAMP-PKA pathway in the pancreas. The interaction between GLP-1 and its receptor is believed to activate adenylate cyclase (AC), which may promote the conversion of ATP into cyclic adenosine monophosphate (cAMP), thereby potentially raising cAMP levels. This increase might activate protein kinase A (PKA) and Rap guanine nucleotide exchange factor 4 (RAPGEF4, also referred to as EPAC2). It is hypothesized that the activated PKA would close the ATP-dependent K+ channels and depolarize the cell membrane, while possibly activating the voltage-dependent Ca2+ channels, leading to Ca2+ inflow and the production of action potentials. Moreover, PKA may facilitate the release of Ca2+ by activating inositol triphosphate (IP3). The activated EPAC2 might also activate Ras protein 1 and phospholipase C, potentially engaging the IP3 and diacylglycerol (DAG) pathways and enhancing the release of Ca2+. Cumulatively, these pathways may increase the intracellular Ca2+ levels, potentially fostering mitochondrial ATP synthesis and promoting insulin release via exocytosis.(7)

Moreover, it appears that by targeting GLP-1 receptors in the gastrointestinal tract, Retatrutide might slow gastric emptying shortly after meals.(8) When Retatrutide interacts with these receptors, it appears to reduce gastric contractions, potentially slowing the transit of food through the digestive system. Additionally, GLP-1 receptor activation might influence the release of various gastrointestinal hormones, such as gastrin, which is involved in regulating gastric acid secretion and motility, and ghrelin, known as the hunger hormone, which is also believed to affect gastric motility. Furthermore, GLP-1 receptor activation may have a direct impact on the stomach's smooth muscle cells, possibly decreasing their contractility and thus delaying gastric emptying.

Similar to the activation of the GIP receptor, it has been suggested that Retatrutide might also affect neurons in the hypothalamic arcuate nucleus, which are involved in the regulation of appetite and hunger, potentially through GLP-1 receptors. These neurons are noted to express proteins such as proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART).(9) It is theorized that direct activation of GLP-1 receptors on POMC/CART neurons might induce feelings of fullness and indirectly inhibit the release of the hunger-stimulating peptides NPY and agouti-related peptide (AgRP). Research also hints that activation of GLP-1 receptors by agonists such as Retatrutide may aid in maintaining higher levels of free leptin and PYY3-36 during weight loss.(10)

Retatrutide and GCG Receptors

GCG receptor activation by agonists like Retatrutide may potentially promote increased energy utilization and fat oxidation, possibly increasing energy expenditure. Studies suggest that Retatrutide might activate the GCG receptors in liver cells, which is purported to boost energy expenditure by increasing the breakdown of fats and possibly enhancing the liver's metabolic rate.(11) This might be achieved through hepatic futile cycling, increased mitochondrial function, and the secretion of thermogenic agents such as fibroblast growth factor 21 (FGF21) and bile acids, which may further enhance energy expenditure. Moreover, the activation of GCG receptors in the liver by Retatrutide might lead to a cascade of metabolic events that support weight loss. This includes the possible reduction of liver fat content through enhanced lipid oxidation, increased activity of metabolic enzymes, and the upregulation of mitochondrial biogenesis. The involvement of key hormones like FGF21 and bile acids, secreted by the liver upon GCG receptor activation, might play a significant role in systemic energy homeostasis.

Retatrutide may also trigger the GCG receptors in fat cells. This activation might initiate a process called beiging, which helps turn white fat cells into beige fat cells. These beige cells, similar to brown fat cells, may burn calories to generate heat, thus possibly increasing thermogenesis and metabolic rate.(12) The beiging of white adipose cells might involve the induction of UCP1-dependent non-shivering thermogenesis and metabolic futile cycles, such as the creatine and succinate cycles, which may waste energy as heat. Additionally, Retatrutide might enhance the expression of thermogenic genes in both brown and beige adipocytes, promoting the formation and activity of these calorie-burning cells. Furthermore, Retatrutide’s action on the GCG receptors might extend to augmenting the thermogenic capacity by potentially leveraging the energy-wasting activities in brown adipose tissue (BAT) cells. The activation of BAT by Retatrutide may increase metabolic rate through the uncoupling protein 1 (UCP1), which possibly dissipates the proton gradient in mitochondria to release energy as heat. This process may utilize stored fats and enhance the oxidation of circulating glucose, lipids, and amino acids, contributing to overall energy expenditure.

Retatrutide peptide is available for research and laboratory purposes only. Please review our Terms and Conditions before ordering.


  1. Folli F, Finzi G, Manfrini R, Galli A, Casiraghi F, Centofanti L, Berra C, Fiorina P, Davalli A, La Rosa S, Perego C, Higgins PB. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am J Physiol Endocrinol Metab. 2023 Nov 1;325(5):E595-E609. doi: 10.1152/ajpendo.00236.2023. Epub 2023 Sep 20. PMID: 37729025; PMCID: PMC10874655.
  2. Jakubowska A, Roux CWL, Viljoen A. The Road towards Triple Agonists: Glucagon-Like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide and Glucagon Receptor - An Update. Endocrinol Metab (Seoul). 2024 Feb;39(1):12-22. doi: 10.3803/EnM.2024.1942. Epub 2024 Feb 14. PMID: 38356208; PMCID: PMC10901658.
  3. Doggrell SA. Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin Investig Drugs. 2023 May;32(5):355-359. doi: 10.1080/13543784.2023.2206560. Epub 2023 Apr 24. PMID: 37086147.
  4. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023 Aug 10;389(6):514-526. doi: 10.1056/NEJMoa2301972. Epub 2023 Jun 26. PMID: 37366315.
  5. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023 Aug 12;402(10401):529-544. doi: 10.1016/S0140-6736(23)01053-X. Epub 2023 Jun 26. PMID: 37385280.
  6. Samms RJ, Sloop KW, Gribble FM, Reimann F, Adriaenssens AE. GIPR Function in the Central Nervous System: Implications and Novel Perspectives for GIP-Based Therapies in Treating Metabolic Disorders. Diabetes. 2021 Sep;70(9):1938-1944. doi: 10.2337/dbi21-0002. Epub 2021 Jun 27. PMID: 34176786; PMCID: PMC8576420.
  7. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne). 2021 Aug 23;12:721135. doi: 10.3389/fendo.2021.721135. PMID: 34497589; PMCID: PMC8419463.
  8. Urva S, O'Farrell L, Du Y, Loh MT, Hemmingway A, Qu H, Alsina-Fernandez J, Haupt A, Milicevic Z, Coskun T. The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying. Diabetes Obes Metab. 2023 Sep;25(9):2784-2788. doi: 10.1111/dom.15167. Epub 2023 Jun 13. PMID: 37311727.
  9. van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014 Dec;63(12):4186-96. doi: 10.2337/db14-0849. Epub 2014 Jul 28. PMID: 25071023.
  10. Ard J, Fitch A, Fruh S, Herman L. Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists. Adv Ther. 2021 Jun;38(6):2821-2839. doi: 10.1007/s12325-021-01710-0. Epub 2021 May 11. PMID: 33977495; PMCID: PMC8189979.
  11. Conceição-Furber E, Coskun T, Sloop KW, Samms RJ. Is Glucagon Receptor Activation the Thermogenic Solution for Treating Obesity? Front Endocrinol (Lausanne). 2022 Apr 25;13:868037. doi: 10.3389/fendo.2022.868037. PMID: 35547006; PMCID: PMC9081793.

Dr. Marinov

Dr. Marinov (MD, Ph.D.) is a researcher and chief assistant professor in Preventative Medicine & Public Health. Prior to his professorship, Dr. Marinov practiced preventative, evidence-based medicine with an emphasis on Nutrition and Dietetics. He is widely published in international peer-reviewed scientific journals and specializes in peptide therapy research.

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