Retatrutide vs MOTS-c: How They Differ
Retatrutide is an investigational hormone-receptor agonist with phase 3 trials in thousands of people, while MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, studied mainly in cells and mice for how muscle handles glucose, exercise and ageing. Both turn up in metabolic research, but they act at different levels: one on hormone receptors on the cell surface, the other on signalling inside the cell. Here is how they compare and what the human evidence on each actually covers.
Findings
- Reta (GLP-3) activates the GIP, GLP-1 and glucagon receptors. In a phase 3 trial of 2,339 adults with obesity, 80 weeks lowered body weight by 25.0% at the highest dose, against 3.9% with placebo (Jastreboff et al., N Engl J Med, 2026).
- MOTS-c is encoded in the mitochondrial 12S rRNA gene. In mice it prevented diet-induced obesity and insulin resistance, acting through the folate cycle and AMPK (Lee et al., Cell Metab, 2015).
- In 10 young men, one cycling session raised MOTS-c 11.9-fold in skeletal muscle and about 1.5-fold in blood, and treatment started late in life raised physical capacity in old mice (Reynolds et al., Nat Commun, 2021).
- The closest MOTS-c work to a clinical trial is a small study of an analogue in adults with obesity and fatty liver, which reported lower liver enzymes and glucose after four weeks (2021).
What is reta (GLP-3)?
Reta is a single peptide built on the GIP hormone backbone, carrying non-natural amino acids and a fatty diacid chain at lysine 17 (Li et al., Cell Discov, 2024). In its discovery work, GIP and GLP-1 receptor activity reduced calorie intake in obese mice and glucagon receptor activity added a rise in energy expenditure (Coskun et al., Cell Metab, 2022). Its half-life is about 6 days (Urva et al., Lancet, 2022). It remains investigational and, at the time of writing, unapproved in Canada and the United States.
The human trials
In the 2023 phase 2 obesity trial (338 adults, 48 weeks), weight fell 24.2% at the highest dose against 2.1% on placebo (Jastreboff et al., N Engl J Med, 2023). In type 2 diabetes, a 537-person phase 3 trial reported HbA1c down 1.94 percentage points against 0.81 on placebo over 40 weeks (Bajaj et al., Lancet, 2026). A DXA substudy found total fat mass down 23.2% to 26.1% in the higher-dose groups at 36 weeks (Coskun et al., Lancet Diabetes Endocrinol, 2025), and in 98 people with fatty liver disease, 86% of the highest-dose group reached normal liver fat by 24 weeks (Sanyal et al., Nat Med, 2024). Side effects were mainly gastrointestinal and mostly mild to moderate.
What is MOTS-c?
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) was identified in 2015 as a 16-amino-acid peptide coded by a short reading frame inside mitochondrial DNA. Its main target appears to be skeletal muscle, where it inhibits the folate cycle and its linked purine synthesis, which activates AMPK, the cell’s energy sensor. In mice it prevented age-dependent and high-fat-diet insulin resistance as well as diet-induced obesity (Lee et al., Cell Metab, 2015). Under metabolic stress it moves into the cell nucleus and regulates nuclear genes, including antioxidant-response genes linked to NRF2 (Kim et al., Cell Metab, 2018). The background is in What Is MOTS-c?
The human data
MOTS-c’s human record is about the body’s own peptide. In a 2021 study, ten sedentary young men cycled on an ergometer: MOTS-c in muscle rose 11.9-fold and stayed raised after four hours of rest, while blood levels rose 1.6-fold during and 1.5-fold after exercise. The same paper found that MOTS-c improved physical performance in young, middle-aged and old mice (Reynolds et al., Nat Commun, 2021), covered in MOTS-c: Exercise, Heat and the Mitochondrial Signal. In 20 lean and obese adults, plasma MOTS-c was similar in both groups and was associated with insulin sensitivity measures in the lean group only (Cataldo et al., J Investig Med, 2018).
An analogue of MOTS-c went through a phase 1a/1b study in adults with obesity and fatty liver disease. After four weeks, the analogue group showed a 21% fall in ALT and a 28% fall in AST (placebo: up 4% and down 11%), and a 6% fall in glucose against no change; weight showed a non-significant downward trend (company-reported topline results, 2021). We found no published controlled trial of MOTS-c itself.
How do reta and MOTS-c compare side by side?
| Question | Reta (GLP-3) | MOTS-c |
|---|---|---|
| What is it? | Synthetic triple hormone receptor agonist | Mitochondrial-derived peptide |
| Size | One acylated peptide on a GIP backbone | 16 amino acids |
| Main research area | Body weight, blood sugar, liver fat | Muscle metabolism, insulin sensitivity, exercise, ageing |
| Mechanism | GIP, GLP-1 and glucagon receptors on the cell surface | Folate cycle, AMPK, nuclear gene regulation inside the cell |
| Human evidence | Phase 2 and phase 3 trials, 2023 to 2026 | Natural-level studies; one small analogue study |
| Forms we supply | 10 mg, 20 mg and 30 mg vials | 10 mg and 40 mg vials |
Which one fits which research question?
- Weight, appetite, HbA1c and liver fat at clinical scale: reta, which has randomised trials measuring each of these.
- Mitochondrial signalling, AMPK and mitonuclear communication: MOTS-c, the peptide that defined the idea of mitochondrial DNA coding for a metabolic hormone.
- Exercise physiology and age-related loss of physical capacity: MOTS-c, whose levels respond to exercise in humans and whose mouse work covers late-life treatment.
- Insulin sensitivity in skeletal muscle: MOTS-c for the cellular mechanism, reta for whole-body glucose outcomes.
Comparing their effect sizes would mislead: reta’s numbers come from large human trials, MOTS-c’s mostly from animals. MOTS-c’s place among other mitochondrial compounds is covered in NAD+ vs MOTS-c, MOTS-c vs SS-31 and 5-Amino-1MQ vs MOTS-c.
Can reta and MOTS-c be studied together?
No published study has combined them. They act at different levels, one at hormone receptors that shape appetite and energy use, the other inside muscle cells through AMPK and gene regulation, so a laboratory design could treat them as separate variables, for example whole-body weight outcomes alongside muscle-level metabolic markers. That rationale comes from each compound’s own literature.
How are they supplied?
Reta comes as 10 mg, 20 mg and 30 mg lyophilised vials; MOTS-c as 10 mg and 40 mg vials, and as part of the Mitochondrial Energy stack. Both are reconstituted with bacteriostatic water (see the MOTS-c reconstitution guide and the peptide calculator), and both follow the general 8 to 12 week fridge window once mixed, detailed in how long reta lasts and how long MOTS-c lasts. Certificates of analysis are on the lab reports page, and every order ships from within Canada by Canada Post Xpresspost.
Reta and MOTS-c are supplied for laboratory research use only. The studies above were clinical and preclinical research using research or pharmaceutical preparations.
Frequently asked questions
What is the difference between reta (GLP-3) and MOTS-c?
Reta is a synthetic peptide that activates the GIP, GLP-1 and glucagon receptors and has phase 3 human trials in obesity and diabetes. MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA that acts inside muscle cells through the folate cycle and AMPK, studied mainly in cells and mice.
Does MOTS-c cause weight loss like reta?
In mice, MOTS-c prevented diet-induced obesity. In humans, the only interventional data come from a small four-week study of an analogue, which reported lower liver enzymes and glucose with a non-significant trend in weight. Reta’s weight data come from randomised trials of thousands of people.
Is MOTS-c a GLP-1?
No. MOTS-c does not act on the GLP-1 receptor. It is a mitochondrial-derived peptide whose studied actions run through the folate cycle, AMPK and regulation of nuclear genes.
Can reta and MOTS-c be studied together?
No published study has combined them. Because one acts at hormone receptors and the other inside muscle cells, a laboratory design using both can keep whole-body and cellular outcomes as separate variables.
Where can I buy reta and MOTS-c in Canada?
Vistara Labs supplies reta (GLP-3) as 10 mg, 20 mg and 30 mg lyophilised vials and MOTS-c as 10 mg and 40 mg vials, with certificates of analysis on the lab reports page, shipped from within Canada by Canada Post Xpresspost.
Product details from vistaralabs.ca, October 2026. Sources: Li W et al. Structural insights into triple agonism at GLP-1R, GIPR and GCGR. Cell Discov. 2024. PMID 39019866. Coskun T et al. Discovery and clinical proof of concept of a triple glucagon, GIP and GLP-1 receptor agonist. Cell Metab. 2022. PMID 35985340. Urva S et al. Phase 1b multiple-ascending-dose trial of a GIP, GLP-1 and glucagon receptor agonist in type 2 diabetes. Lancet. 2022. PMID 36354040. Jastreboff AM et al. Phase 2 trial of a triple-hormone-receptor agonist for obesity. N Engl J Med. 2023. PMID 37366315. Jastreboff AM et al. Phase 3 trial of a triple hormone receptor agonist for obesity. N Engl J Med. 2026. PMID 42814954. Bajaj HS et al. Phase 3 trial of a GIP, GLP-1 and glucagon receptor agonist in type 2 diabetes. Lancet. 2026. PMID 42250575. Coskun T et al. Body composition substudy of a phase 2 trial in type 2 diabetes. Lancet Diabetes Endocrinol. 2025. PMID 40609566. Sanyal AJ et al. Triple hormone receptor agonist for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024. PMID 38858523. Lee C et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015. PMID 25738459. Kim KH et al. The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab. 2018. PMID 29983246. Reynolds JC et al. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun. 2021. PMID 33473109. Cataldo LR et al. Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med. 2018. PMID 29593067. Topline results of the phase 1a/1b study of the MOTS-c analogue CB4211 in obese adults with NAFLD, company announcement, 2021.
More on this: What Is MOTS-c? The Peptide Encoded in Mitochondrial DNA and Peptides for Weight Loss: What People Actually Mean.
All products supplied by Vistara Labs are intended for laboratory research use only. They are not drugs, are not approved for human or veterinary use, and are not intended to diagnose, treat, cure or prevent any condition. Nothing on this page constitutes medical advice or guidance for use in humans.
