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Comparisons11 min read

Fragment 176-191 vs. AOD-9604: Fat Loss Peptides

These two peptides are so closely related that some people use their names interchangeably. That's a mistake. Fragment 176-191 and AOD-9604 share a common origin -- both are derived from the tail end of human growth hormone -- and they target the same fat-burning pathway.

These two peptides are so closely related that some people use their names interchangeably. That's a mistake. Fragment 176-191 and AOD-9604 share a common origin -- both are derived from the tail end of human growth hormone -- and they target the same fat-burning pathway. But they differ in a single structural modification that changes their stability, bioavailability, and clinical history in meaningful ways. Both went through real pharmaceutical development. Both showed strong fat-loss effects in animals. And both ultimately failed to prove themselves in the largest human trials. Their story is a useful case study in the gap between promising mechanism and proven therapy.

Table of Contents

The Origin: Growth Hormone's Fat-Burning Fragment

Human growth hormone (HGH) is a 191-amino-acid protein that does many things simultaneously. It stimulates growth, builds muscle, strengthens bones, influences blood sugar metabolism, and burns fat. For decades, researchers have tried to isolate specific functions of HGH into smaller, more targeted molecules.

The fat-burning activity of HGH was mapped to its C-terminal region -- specifically, amino acids 176 through 191. This 16-amino-acid stretch doesn't bind to growth hormone receptors (which mediate growth, IGF-1 production, and glucose effects) but does activate lipolytic (fat-burning) pathways in adipose tissue.

That was an exciting discovery. It meant, in theory, that you could get HGH's fat-burning benefits without its side effects: no IGF-1 elevation, no insulin resistance, no abnormal tissue growth.

Both Fragment 176-191 and AOD-9604 are attempts to turn that theory into a drug.

Fragment 176-191: The Original Sequence

Fragment 176-191 is a straightforward synthetic copy of amino acids 176-191 of human growth hormone. No modifications, no additions. It's the native sequence, reproduced in a lab.

As a linear peptide -- a simple chain without any structural reinforcement -- Fragment 176-191 is vulnerable to degradation. Enzymes in blood plasma can break it down quickly. This limits its effective duration of action and creates challenges for consistent dosing.

The research on Fragment 176-191 established the foundational science. A 2008 study published in the Journal of Endocrinology confirmed that the fragment increased lipid oxidation without stimulating IGF-1 or activating GH signaling pathways. It demonstrated the core concept: you could isolate fat-burning from the rest of growth hormone's effects.

AOD-9604: The Stabilized Version

AOD-9604 is a modified version of HGH Fragment 176-191, developed by Metabolic Pharmaceuticals Ltd. in Australia during the 1990s. The name stands for "Anti-Obesity Drug, compound 9604."

AOD-9604 contains amino acids 177-191 (one amino acid shorter than Fragment 176-191) with a tyrosine residue added at the N-terminus. More importantly, AOD-9604 features a disulfide bridge between two cysteine residues. This cyclization is the key difference: it makes the peptide significantly more resistant to enzymatic breakdown in blood plasma, improving bioavailability.

AOD-9604 was developed with pharmaceutical intent. It went through formal preclinical development, toxicology studies, and six human clinical trials involving over 900 participants. This level of clinical development is unusual for peptides in this category.

Structural Differences

FeatureFragment 176-191AOD-9604
Amino Acid SequenceHGH residues 176-191 (16 amino acids)HGH residues 177-191 + tyrosine (16 amino acids)
StructureLinear peptide chainCyclized with disulfide bridge
Key ModificationNone (native sequence)Tyrosine substitution at N-terminus; disulfide bridge
StabilityLower (susceptible to proteolytic enzymes)Higher (disulfide bridge protects against degradation)
BioavailabilityLowerHigher (more resistant to plasma degradation)
Development StatusResearch compoundWent through formal pharmaceutical development
Clinical TrialsLimited6 human trials (~900 participants)

The structural differences matter practically. AOD-9604's cyclization means more of the injected or ingested dose reaches adipose tissue intact. For an orally administered peptide (AOD-9604 was tested as an oral drug), this kind of stability advantage is even more significant, since the gastrointestinal tract is harsh on unprotected peptides.

How They Burn Fat: The Beta-3 Adrenergic Pathway

Both peptides share the same core mechanism: they activate fat burning through the beta-3 adrenergic receptor (beta-3-AR) pathway.

A key study by Heffernan et al. (2001) demonstrated this mechanism clearly. Both human GH and AOD-9604 reduced body weight and body fat in obese mice after 14 days of chronic administration. The fat loss correlated with increased expression of beta-3-AR RNA, the major lipolytic receptor on fat cells. Both compounds raised the depressed beta-3-AR expression in obese mice back to levels comparable with lean mice.

The mechanism works through several steps:

  1. Beta-3-AR upregulation: The peptides increase the expression of beta-3 adrenergic receptors on fat cells. These receptors are the primary trigger for lipolysis (fat breakdown) in adipose tissue.

  2. Hormone-sensitive lipase activation: Both peptides stimulate hormone-sensitive lipase, the enzyme that breaks triglycerides (stored fat) into free fatty acids that can be burned for energy.

  3. Acetyl-CoA carboxylase inhibition: They inhibit acetyl-CoA carboxylase, an enzyme involved in fat synthesis. This creates a dual action: more fat burning and less new fat creation.

  4. cAMP-dependent signaling: The peptides initiate a cascade of cAMP-dependent enzyme activations that promote fat oxidation and energy release.

An important detail from the knockout mouse studies: mice genetically modified to produce no beta-3-AR do not respond to the lipolytic effects of either HGH or Fragment 176-191. This confirmed that the beta-3-AR pathway is essential to their fat-burning mechanism.

What They Don't Do: IGF-1 and Blood Sugar

The selectivity of both peptides is their most significant pharmacological feature. The C-terminal region of growth hormone (amino acids 176-191) does not participate in growth hormone receptor binding. By isolating only this fragment, both peptides lack the structural features needed to bind GH receptors.

This means:

  • No IGF-1 increase: Clinical trials measuring serum IGF-1 in approximately 900 AOD-9604 participants found zero change at all doses tested. A 2013 safety study confirmed the peptide did not affect serum IGF-1 levels.

  • No blood sugar disruption: Unlike full-length growth hormone, which can cause insulin resistance and glucose intolerance, neither Fragment 176-191 nor AOD-9604 had negative effects on carbohydrate metabolism in any study. A randomized trial found AOD-9604 showed good short-term tolerability without significantly changing glucose levels.

  • No abnormal tissue growth: Without GH receptor binding, there's no stimulation of the growth pathways that can lead to organomegaly (enlarged organs) or other growth-related side effects of HGH.

This clean separation of fat-burning from growth signaling was the entire scientific premise behind their development. On this front, both peptides delivered exactly as designed.

Animal Research: Strong Results

The preclinical data for both peptides was genuinely promising.

Weight loss in obese mice: After 14 days of chronic intraperitoneal administration, both HGH and AOD-9604 significantly reduced body weight and body fat in obese mice. Studies showed a nearly 50% reduction in weight gain in obese animals over a three-week treatment course.

Adipocyte size reduction: Chronic treatment of obese Zucker rats with AOD-9604 for 20 days reduced average adipocyte (fat cell) diameter from 110 to 80 micrometers -- a meaningful physical shrinkage of fat cells.

Selective effect on obese subjects: The weight loss effects were seen only in obese mice. Lean mice maintained normal body weight even when exposed to the peptides. This suggests a regulatory pathway that activates fat loss only when body fat is above normal levels, then stops when weight normalizes.

Beta-3-AR dependency: The knockout mouse experiments confirmed the mechanism was beta-3-AR dependent, and the effect restored fat cell receptor expression in obese mice to levels matching lean controls.

These results looked exactly like what you'd want from a targeted fat-loss drug: effective in the overweight, safe in the lean, no hormonal side effects, and a clear mechanism.

Human Clinical Trials: The Disappointing Reality

AOD-9604's clinical journey is a sobering lesson in the gap between animal models and human medicine.

The Early Promise (Phase II, 12 weeks)

The first major human trial enrolled 300 obese patients across five sites. Participants took AOD-9604 orally once daily for 12 weeks at six doses: 0 mg (placebo), 1 mg, 5 mg, 10 mg, 20 mg, and 30 mg.

Results: The 1 mg dose group lost an average of 2.8 kg over 12 weeks -- more than triple the 0.8 kg lost by placebo. The trial also showed small but consistent improvements in cholesterol profiles and reduced glucose intolerance.

A separate analysis of 34 patients on low-dose oral AOD-9604 confirmed significant weight loss and improved glucose tolerance compared to 37 placebo patients.

These results were encouraging enough to fund a larger trial.

The Failure (Phase IIb OPTIONS Trial, 24 weeks)

The OPTIONS trial was the definitive test. It enrolled 536 obese subjects in a randomized, double-blind, placebo-controlled design. Dose groups of 0 (placebo), 0.25, 0.5, and 1 mg were tested over 24 weeks.

The trial failed. AOD-9604 did not produce statistically significant weight loss compared to placebo.

One possible explanation: the OPTIONS trial incorporated an intensive diet and exercise program for all participants, including the placebo group. The weight loss from lifestyle modification may have overwhelmed any additional effect from the peptide.

Development of AOD-9604 for obesity was terminated in 2007.

Fragment 176-191 Human Data

Fragment 176-191 has far less human clinical data than AOD-9604. A 3-month clinical trial showed it promoted more significant body weight loss compared to placebo, but the results from a 2007 trial did not confirm efficacy. The dataset is too small and inconsistent to draw firm conclusions.

Side-by-Side Comparison

FactorFragment 176-191AOD-9604
OriginAmino acids 176-191 of HGHModified amino acids 177-191 of HGH
StabilityLow (linear, unprotected)Higher (cyclized, disulfide bridge)
MechanismBeta-3-AR upregulation, lipolysisBeta-3-AR upregulation, lipolysis
IGF-1 EffectNoneNone (confirmed in ~900 patients)
Blood Sugar EffectNoneNone (confirmed in clinical trials)
Animal Fat Loss DataStrongStrong
Human Fat Loss DataLimited, mixedPromising at 12 weeks; failed at 24 weeks
Total Human Subjects StudiedLimited~900 across 6 trials
Safety ProfileGood (limited data)Well-documented; minimal adverse effects
FDA ApprovalNoNo
GRAS StatusNoYes (for food/supplement use)
Administration Routes TestedSubcutaneous injectionOral, subcutaneous, intranasal

Why Animal Results Didn't Translate

The failure of AOD-9604 in its largest human trial deserves honest examination. Several factors likely contributed:

1. Human beta-3-AR differences: Beta-3 adrenergic receptors play a larger role in rodent fat metabolism than in human fat metabolism. Humans have fewer beta-3-AR receptors in adipose tissue relative to beta-1 and beta-2 receptors. A mechanism that dominates fat burning in mice may produce only a modest signal in humans.

2. Isolated lipolytic effect: Growth hormone's fat-burning effects in the body involve multiple pathways working simultaneously: IGF-1 signaling, direct metabolic effects, appetite regulation, and the lipolytic fragment's beta-3-AR activity. When you isolate just the C-terminal fragment, you get only one piece of a multi-component system. That single piece may not be potent enough alone.

3. Trial design: The OPTIONS trial's intensive lifestyle intervention for all groups (including placebo) may have created a ceiling effect. When everyone is losing weight from diet and exercise, the marginal benefit of an additional fat-loss mechanism may be too small to detect.

4. Dose-response paradox: The earlier 12-week trial showed the best results at 1 mg. The OPTIONS trial used 0.25, 0.5, and 1 mg. It's possible the optimal dose wasn't adequately captured, or that the dose-response relationship is non-linear.

5. Oral bioavailability: Despite AOD-9604's improved stability over Fragment 176-191, oral peptide delivery is still challenging. Some researchers question whether enough intact peptide reached adipose tissue to produce meaningful effects at the doses used.

Current Status and Regulatory Picture

Neither peptide is FDA-approved for any therapeutic indication. Neither is approved for weight loss by any major health authority worldwide.

AOD-9604 received "generally recognized as safe" (GRAS) status for use in foods, drinks, and dietary supplements -- a lower regulatory bar than drug approval. This GRAS designation was conditional on publication of pre-existing safety data. It does not mean AOD-9604 is approved as a weight loss treatment.

Fragment 176-191 has no comparable regulatory recognition.

Both peptides exist in a gray area: available from research supply companies, used in some clinical settings outside the U.S., but lacking the regulatory approval that would make them standard medical treatments.

For context, the GLP-1 agonists that dominate today's obesity treatment market -- semaglutide and tirzepatide -- produce weight loss of 15-21% of body weight in clinical trials. Even AOD-9604's best result (2.8 kg over 12 weeks in the early trial) is modest by comparison.

The Bottom Line

Fragment 176-191 and AOD-9604 are two versions of the same idea: isolate growth hormone's fat-burning mechanism and deliver it without GH's side effects. On the mechanism side, they succeeded. Both peptides burn fat through beta-3 adrenergic receptor upregulation without affecting IGF-1, blood sugar, or tissue growth. Their safety profiles, documented across over 900 human subjects (for AOD-9604), are genuinely clean.

On the efficacy side, the results are disappointing. Animal studies consistently showed strong fat loss. But AOD-9604 failed its largest human trial, and Fragment 176-191's human data is too limited to be conclusive.

Between the two, AOD-9604 is the more developed compound: better stability, more human safety data, GRAS status, and a full pharmaceutical development history. Fragment 176-191 is the simpler, less stable original with a thinner evidence base.

But neither has earned a place as a proven fat-loss therapy. The isolated lipolytic effect of HGH's C-terminal fragment, while real in the lab, may simply not be powerful enough on its own to produce meaningful weight loss in humans. In a world where GLP-1 agonists produce 15-21% body weight reductions with robust clinical evidence, the case for these peptides as standalone fat-loss agents is difficult to make.

They remain scientifically interesting as probes of fat metabolism and as evidence that growth hormone's functions can be pharmacologically dissected. Whether they'll find a clinical role -- perhaps in combination with other agents or in specific patient populations -- remains an open question.

References

  1. Heffernan, M.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. https://pubmed.ncbi.nlm.nih.gov/11713213/

  2. More, M.I., et al. "Safety and Metabolism of AOD9604, a Novel Nutraceutical Ingredient for Improved Metabolic Health." Journal of Endocrinology and Metabolism, 2014. https://jofem.org/index.php/jofem/article/view/213/278

  3. Stier, H., et al. "Effects of oral administration of synthetic fragment of human growth hormone on lipid metabolism." Hormone and Metabolic Research, 2000. https://www.researchgate.net/publication/12369792

  4. Thompson, D., et al. "The effect of AOD9604 on weight loss in obese adults: Results of a randomized, double-blind, placebo-controlled, multicenter study." Obesity Research, 2007. https://www.researchgate.net/publication/295313034

  5. "Obesity Pharmacotherapy: Current Perspectives and Future Directions." Translational Research, 2013. https://pmc.ncbi.nlm.nih.gov/articles/PMC3584306/

  6. "Obesity drug codenamed AOD9604 highly successful in trials." News Medical, 2004. https://www.news-medical.net/news/2004/12/16/6878.aspx

  7. Lee, E. "SAVING AOD9604." PCAC Meeting Presentation, FDA-2024-N-4777, December 4, 2024. https://downloads.regulations.gov/FDA-2024-N-4777-0009/attachment_9.pdf

  8. "Fragment 176-191 Peptide and Weight Studies." Core Peptides Research Review. https://www.corepeptides.com/fragment-176-191-peptide-and-studies-in-weight/

  9. "AOD 9604 Peptide: Research Overview, Mechanisms, and Emerging Insights." Drip Hydration, 2024. https://driphydration.com/blog/aod-9604-guide/

  10. "AOD-9604 Selective Action: Fat Loss Without IGF-1 or Blood Sugar Effects." Beverly Hills Rejuvenation Center. https://www.bhrcenter.com/med-spa-blog/aod-9604-selective-action-fat-loss-without-igf-1-or-blood-sugar-effects/