AOD-9604, the Growth Hormone Fragment That Slimmed Obese Mice and Disappointed in People

Patients usually ask me about AOD-9604 after they've seen it described as the fat-burning piece of growth hormone with the side effects cut away. That description is a fair summary of the idea behind the drug, but it leaves out that the idea was tested in more than 500 people nearly twenty years ago, that the trial missed its weight-loss endpoint, and that the company that owned the drug ended the program.

An elegant idea from Monash University

The idea behind AOD-9604 is that growth hormone's fat-burning action can be separated from its other effects. Growth hormone drives lipolysis, the breakdown of stored fat, and it also raises blood sugar and insulin-like growth factor 1 (IGF-1), the hormone that carries out most of its growth-promoting work. Frank Ng's laboratory at Monash University in Melbourne proposed that these actions live in different parts of the molecule, with the fat-related action in the tail end, amino acids 177 to 191. In 1994 his group reported that a synthetic copy of that fragment reduced cumulative weight gain and fat mass in genetically obese mice, and they suggested it might one day treat human obesity and improve meat quality in farm animals [1]. AOD-9604, short for anti-obesity drug 9604, is that same fragment with a tyrosine added to its front end [2].

Obese rodents gained less weight

In obese rodents the fragment did what the theory predicted. Ng and colleagues gave obese Zucker rats a daily oral dose of 500 micrograms per kilogram for 19 days and cut their weight gain by more than half, 15.8 grams against 35.6 grams in controls. The treated rats showed more lipolytic activity in their fat tissue and, unlike rats given intact growth hormone, no loss of insulin sensitivity on the euglycemic clamp, the reference test for measuring it [3]. In obese mice treated for 14 days, both growth hormone and AOD-9604 reduced weight gain and increased fat oxidation, yet only growth hormone raised blood sugar and suppressed insulin secretion, and AOD-9604 neither bound the growth hormone receptor nor made cells proliferate [4].

The mechanism appeared to involve the beta-3 adrenergic receptor, the main receptor through which adrenaline-like signals tell a fat cell to release its fat. Obese mice carry depressed levels of beta-3 receptor RNA in their fat, and 14 days of AOD-9604 restored those levels to the range seen in lean mice. Mice engineered to lack the receptor didn't lose weight on long-term treatment, even though a single dose still raised their energy expenditure and fat oxidation [5]. The authors concluded that the peptide doesn't act directly through the beta-3 receptor, and that by raising the receptor's expression it may make fat cells more sensitive to the body's own lipolytic signals [5].

These were genetically obese animals treated for two or three weeks, and the outcome was slower weight gain, which isn't the same as an overweight adult losing fat they already carry.

The human trial didn't deliver

The human program started with promise and ended without a peer-reviewed efficacy paper. A Melbourne company, Metabolic Pharmaceuticals, took the peptide into development for obesity, and by February 2002 phase 2a trials were underway [6]. According to a 2026 review in Frontiers in Endocrinology by Dominikowski and colleagues, the human studies were short, participants tolerated the drug well with mild and transient complaints such as headache and fatigue, and it didn't meaningfully change IGF-1 or glucose tolerance, which is what the theory predicted [7]. Efficacy is where the program failed, because in a 24-week study of the oral drug that enrolled 534 people and randomized 502, AOD-9604 showed no significant benefit on the primary weight-loss endpoint [7]. In 2007 the sponsor announced that the results didn't support commercial viability and terminated the obesity program [7].

The same review points out that what we know about this trial comes from the sponsor's own announcements and not from a peer-reviewed report [7]. I searched PubMed for the trial and found nothing, and a 2013 safety and tolerability paper appeared in a journal PubMed doesn't index. When the encouraging rodent data appear in Endocrinology and the decisive human trial never appears anywhere, I read that silence as information. The human studies also tested an oral drug and single intravenous doses [7], so as far as I can find, the subcutaneous injection that compounding pharmacies prepare has never been through a published efficacy trial of any kind.

Why would a fragment that worked in rats fail in people? I hypothesize that part of the answer lies in the beta-3 receptor itself. Drugs that stimulate that receptor are highly effective anti-obesity agents in rodents, yet human fat carries lower levels of beta-3 receptor RNA than rodent fat, and adult humans have little brown fat, one of the main tissues where those drugs act [8]. A peptide that works by restoring beta-3 signaling depends on machinery that rodents have in abundance and we have far less of.

The cartilage detour

After the obesity program ended, interest shifted to joints, on thinner evidence still. Kwon and Park, in a 2015 study in Annals of Clinical and Laboratory Science, induced knee osteoarthritis in 32 rabbits with collagenase and then injected the joints weekly with saline, hyaluronic acid, 0.25 mg of AOD-9604, or both. Every treatment beat saline on gross and microscopic cartilage scores, the combination scored best, and the rabbits that received it limped for the shortest time [9]. That's one rabbit study using ultrasound-guided injections placed directly into the joint, and no convincing human trial has tested AOD-9604 for osteoarthritis or tissue repair [7]. An injection under the skin of your abdomen for a sore knee has no evidence behind it.

How it compares with a GLP-1

GLP-1 medications have the randomized evidence that AOD-9604 lacks. In SURMOUNT-1, 2,539 adults with obesity or overweight took tirzepatide or placebo for 72 weeks, and average weight fell by 15.0 to 20.9 percent depending on the dose, against 3.1 percent with placebo [10]. Those drugs carry their own problems, including regain when you stop, but nobody has to guess whether they work. If you need to lose a meaningful amount of fat and want a medication to help, the evidence supports a GLP-1 and doesn't support AOD-9604.

Safety and who shouldn't use it

The short-term human data raised no alarm, and no long-term safety data exist [7]. The same review noted that the FDA has flagged the compound over immunogenicity, the possibility that the body forms antibodies against an injected synthetic peptide [7]. Compounded AOD-9604 isn't FDA-approved for any use, and its parent molecule, recombinant growth hormone, is approved for growth hormone deficiency and not for fat loss (we cover the peptides that raise your own growth hormone in our post on CJC-1295 and ipamorelin). I won't prescribe AOD-9604 during pregnancy or breastfeeding, or to anyone under 18, because nobody has studied it in those groups. The World Anti-Doping Agency bans it and laboratories can detect it in urine [2], so competitive athletes should stay away.

What this means if you're considering it

This means you should expect little from AOD-9604, and that the measures with the most evidence for fat loss don't come in a vial.

• Measure the right thing. Body fat and muscle predict your health better than the scale does, and fasting insulin tells you whether your metabolism is improving underneath.
• Do the basics first. Eat a protein-forward diet of single-ingredient whole foods, lift weights, walk daily, and protect your sleep.
• If obesity is harming your health and you want a medication, choose the one with trials behind it.
• If you still want to try AOD-9604, perhaps because you're close to your goal or can't tolerate a GLP-1, treat it as a defined experiment. We measure body composition and fasting insulin beforehand, set an end date, repeat the measurements, and stop if nothing has changed.

AOD-9604 is a useful lesson in how drug development is supposed to work. A sound idea produced encouraging rodent data, a company paid for a human trial in more than 500 people, and the trial came back negative. I'd rather you hear that from me before you pay for it than discover it afterward, and the references below let you check my reading against the sources.

Ask a provider about AOD-9604

References

1. Natera SH, Jiang WJ, Ng FM. Reduction of cumulative body weight gain and adipose tissue mass in obese mice: response to chronic treatment with synthetic hGH 177-191 peptide. Biochem Mol Biol Int. 1994. PMID: 7987248
2. Cox HD, Smeal SJ, Hughes CM, et al. Detection and in vitro metabolism of AOD9604. Drug Test Anal. 2015. PMID: 25208511
3. Ng FM, Sun J, Sharma L, et al. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000. PMID: 11146367
4. Heffernan MA, Thorburn AW, Fam B, et al. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001. PMID: 11673763
5. 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. PMID: 11713213
6. Wilding J. AOD-9604 Metabolic. Curr Opin Investig Drugs. 2004. PMID: 15134286
7. Dominikowski A, Rękoś Z, Olejarz M, et al. The emerging landscape of performance-enhancing peptides modulating GH-IGF1 axis: bridging the gap between clinical evidence and patient self-administration. Front Endocrinol (Lausanne). 2026. PMID: 42395176
8. Arch JR. beta(3)-Adrenoceptor agonists: potential, pitfalls and progress. Eur J Pharmacol. 2002. PMID: 12007528
9. Kwon DR, Park GY. Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model. Ann Clin Lab Sci. 2015. PMID: 26275694
10. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022. PMID: 35658024