Metabolic & Weight

Metabolic research peptides and small molecules are compounds investigated in the peer-reviewed literature across body-weight, glycemic-control, mitochondrial-energetics, and adipose-tissue models. Research has investigated the following compounds in the context of metabolic-related preclinical and clinical models: Semaglutide, Tirzepatide, Retatrutide, Orforglipron, Tesamorelin, AOD-9604, Tesofensine, 5-Amino-1MQ, BAM15, SLU-PP-332, and MOTS-c.

Unlike most peptide-research categories, the metabolic literature includes several compounds with extensive Phase III human clinical data and active regulatory approvals — notably the GLP-1/GIP/glucagon receptor agonist family (semaglutide, tirzepatide, retatrutide) and the GHRH analog tesamorelin (approved for HIV-associated lipodystrophy). Several other compounds in this category — 5-Amino-1MQ, BAM15, SLU-PP-332 — remain in preclinical investigation.

What Peer-Reviewed Research Investigates in This Category

Metabolic-category research in the published literature investigates several mechanistic targets:

  • Incretin-receptor agonism — GLP-1, GIP, and glucagon receptor pharmacology, with monoagonists (semaglutide), dual agonists (tirzepatide), and triple agonists (retatrutide) advancing through Phase III obesity and type 2 diabetes trials. Orforglipron is a non-peptide oral small-molecule GLP-1 receptor agonist in Phase III development.
  • Mitochondrial uncoupling — protonophore compounds (BAM15) that dissipate the mitochondrial proton gradient, investigated in rodent obesity and hepatic-steatosis models.
  • NNMT inhibition — nicotinamide N-methyltransferase inhibitors (5-Amino-1MQ) investigated in diet-induced obese rodents for adipose-tissue metabolic effects.
  • ERR-α/γ agonism — estrogen-related receptor agonists (SLU-PP-332) investigated in rodent endurance and metabolic-flux models.
  • Monoamine reuptake inhibition — triple monoamine reuptake inhibitors (tesofensine), with published Phase II obesity data.
  • GH/IGF-1 axis modulation — GHRH analogs (tesamorelin) and lipolytic GH fragments (AOD-9604).
  • Mitochondrial-derived peptides — endogenous mitokines (MOTS-c) investigated in insulin-sensitivity and exercise-mimetic models.

Compounds Studied in Metabolic Research

Semaglutide (GLP-1)

Semaglutide is a long-acting GLP-1 receptor agonist with a C18 fatty-acid acyl side chain for albumin binding. The STEP trial program (Wilding et al., NEJM 2021) demonstrated clinically significant weight reduction in adults with obesity at 2.4 mg weekly administration.1 FDA-approved for type 2 diabetes (2017) and for chronic weight management in obesity (2021).

Full Semaglutide research summary →

Tirzepatide (GLP-2)

Tirzepatide is a dual GIP/GLP-1 receptor agonist. The SURMOUNT-1 trial (Jastreboff et al., NEJM 2022) reported placebo-subtracted mean weight reduction of approximately 17–21% over 72 weeks in adults with obesity.2 FDA-approved for type 2 diabetes (2022) and for chronic weight management in obesity (2023).

Full Tirzepatide research summary →

Retatrutide (GLP-3)

Retatrutide is an investigational triple agonist at the GLP-1, GIP, and glucagon receptors. The Phase 2 obesity trial (Jastreboff et al., NEJM 2023) reported mean weight reduction of approximately 24% at the 12 mg amount over 48 weeks.3 Phase III TRIUMPH program ongoing as of 2026; not yet FDA-approved.

Full Retatrutide research summary →

Orforglipron

Orforglipron is an oral non-peptide small-molecule GLP-1 receptor agonist developed by Eli Lilly. Phase 2 obesity data (Wharton et al., NEJM 2023) reported mean weight reduction of approximately 14.7% at 36 weeks.4 ACHIEVE and ATTAIN Phase III programs are ongoing.

Full Orforglipron research summary →

Tesamorelin

Tesamorelin is a stabilized GHRH(1–44) analog FDA-approved for HIV-associated lipodystrophy. The pivotal trials (Falutz et al., NEJM 2007) demonstrated reductions in visceral adipose tissue in HIV-infected adults.5 Also classified under growth-hormone research.

Full Tesamorelin research summary →

AOD-9604

AOD-9604 is a synthetic fragment (residues 176–191) of human growth hormone, originally developed by Metabolic Pharmaceuticals as an oral anti-obesity candidate. Early metabolic and lipolytic-mechanism work characterized the fragment’s pharmacology (Ng et al., 2000) and downstream beta-3 adrenergic receptor signaling (Heffernan et al., 2001).6 The Metabolic Pharmaceuticals Phase IIb obesity development program did not demonstrate meaningful weight reduction at the amounts tested, and the obesity development program was subsequently discontinued. Later research has investigated lipolytic and chondroprotective effects in preclinical models.

Full AOD-9604 research summary →

Tesofensine

Tesofensine is a triple monoamine reuptake inhibitor (serotonin, norepinephrine, dopamine) originally developed for Alzheimer’s and Parkinson’s disease. The Phase II TIPO-1 obesity trial (Astrup et al., Lancet 2008) reported mean weight reduction of approximately 9.2% at 1.0 mg over 24 weeks.7 Tesofensine has received marketing authorization in Mexico for obesity (as a combination product with metoprolol developed by Saniona). Not FDA-approved.

Full Tesofensine research summary →

5-Amino-1MQ

5-Amino-1MQ is a small-molecule inhibitor of nicotinamide N-methyltransferase (NNMT), an enzyme expressed in adipose tissue at elevated levels in obesity. Neelakantan et al. (2018) reported that NNMT inhibition with 5-Amino-1MQ reduced fat mass in diet-induced obese mice without altering food intake or lean mass.8 Preclinical only.

Full 5-Amino-1MQ research summary →

BAM15

BAM15 is a mitochondrial protonophore that uncouples oxidative phosphorylation from ATP synthesis, dissipating the proton gradient as heat. Kanemoto et al. (2019) and Alexopoulos et al. (2020) reported reductions in body weight and hepatic steatosis in diet-induced obese mice with no observed effect on body temperature in the amount ranges studied.9 Preclinical only.

Full BAM15 research summary →

SLU-PP-332

SLU-PP-332 is a synthetic agonist of the estrogen-related receptors (ERRα, ERRβ, ERRγ). Billon et al. (2023, J Med Chem) reported that SLU-PP-332 administration increased exercise capacity, mitochondrial biogenesis, and oxidative metabolism in mice — characterized in lay press as an “exercise mimetic.”10 Preclinical only.

Full SLU-PP-332 research summary →

MOTS-c

MOTS-c is a 16-amino-acid mitochondrial-derived peptide encoded within the 12S rRNA region of mitochondrial DNA. Lee et al. (2015, Cell Metab) characterized MOTS-c as a regulator of insulin sensitivity and metabolic homeostasis in mice.11 Also investigated in longevity contexts.

Full MOTS-c research summary →

Frequently Asked Research Questions

What peptides and compounds are studied for metabolic and weight-related research?

The peer-reviewed metabolic-research literature focuses on the GLP-1 receptor agonist family (semaglutide, tirzepatide, retatrutide, orforglipron), the GHRH analog tesamorelin, the GH-fragment AOD-9604, the monoamine reuptake inhibitor tesofensine, the NNMT inhibitor 5-Amino-1MQ, the mitochondrial uncoupler BAM15, the ERR agonist SLU-PP-332, and the mitochondrial-derived peptide MOTS-c.

Which metabolic compounds have Phase III clinical data?

Semaglutide and tirzepatide have completed Phase III trials and are FDA-approved for type 2 diabetes and obesity. Tesamorelin has completed Phase III and is FDA-approved for HIV-associated lipodystrophy. Retatrutide and orforglipron are in active Phase III programs as of 2026. Tesofensine has published Phase III data and has received marketing authorization in Mexico (as a combination product with metoprolol) but is not FDA-approved.

What is the difference between semaglutide, tirzepatide, and retatrutide?

Semaglutide is a GLP-1 receptor monoagonist. Tirzepatide is a dual GIP/GLP-1 receptor agonist. Retatrutide is a triple GLP-1/GIP/glucagon receptor agonist. Each subsequent generation adds receptor targets investigated for additive metabolic effects. Magnitude of weight reduction in published Phase II/III obesity trials increases across this sequence in head-to-head and cross-trial comparisons.

Are 5-Amino-1MQ, BAM15, and SLU-PP-332 in clinical trials?

No published human clinical trials of 5-Amino-1MQ, BAM15, or SLU-PP-332 had reported as of 2026. The published evidence base for each compound is preclinical, consisting of rodent metabolic-model studies and in vitro mechanism work.

Why is tesamorelin classified under both metabolic and growth-hormone research?

Tesamorelin is a stabilized GHRH(1–44) analog — pharmacologically a growth-hormone-axis compound — but its FDA-approved indication and primary clinical research literature concern visceral adipose tissue reduction in HIV-associated lipodystrophy, a metabolic indication. It appears in both category hubs for that reason.

References

  1. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002. PubMed.
  2. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205–216. PubMed.
  3. Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a Phase 2 trial. N Engl J Med. 2023;389(6):514–526. PubMed.
  4. Wharton S, Blevins T, Connery L, et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877–888. PubMed.
  5. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357(23):2359–2370. PubMed.
  6. Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274–278. Heffernan M, Summers RJ, Thorburn A, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice. Endocrinology. 2001;142(12):5182–5189. PubMed.
  7. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9653):1906–1913. PubMed.
  8. Neelakantan H, Vance V, Wetzel MD, et al. Selective and membrane-permeable small-molecule inhibitors of nicotinamide N-methyltransferase reverse high-fat-diet-induced obesity in mice. Biochem Pharmacol. 2018;147:141–152. PubMed.
  9. Alexopoulos SJ, Chen S-Y, Brandon AE, et al. Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice. Nat Commun. 2020;11(1):2397. PubMed.
  10. Billon C, Sitaula S, Banerjee S, et al. Synthetic ERR agonists augment exercise responses in mice. J Med Chem. 2023 (and companion publications). PubMed.
  11. Lee C, Zeng J, Drew BG, et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015;21(3):443–454. PubMed.