AOD-9604

Growth hormone does two quite different things: it drives growth through IGF-1, and it mobilizes fat. Work at Monash University in the 1980s and 1990s localized the metabolic activity to the C-terminal end of the molecule, and showed that a synthetic peptide of residues 177-191 reproduced the antilipogenic effect [3] and reduced weight gain and fat mass in obese mice [4]. AOD-9604 is that fragment (in the 176-191 numbering, with a tyrosine added at the N terminus) developed as a drug candidate.

Two development codes. The Monash papers do not all describe the same molecule. The 1993-2000 work is reported under the code AOD-9401 [1][5]; only from 2001 does AOD9604 appear [2]. The papers themselves never state how the two relate, so results are attributed below to whichever code the paper used, and the two should not be treated as interchangeable.

What it does in animals. Thirty days of oral AOD-9401 in ob/ob mice slowed weight gain from day 16 onward without changing food intake, cut lipogenic activity and raised lipolytic activity in fat tissue, and raised energy expenditure and fat oxidation acutely [1]. Twenty days of AOD-9401 in obese Zucker rats reduced weight gain and shrank the average fat cell from 110 to 80 µm across, and - unlike growth hormone itself - produced neither insulin resistance nor glucose intolerance [5]. Fourteen days of intraperitoneal AOD9604 reduced body weight and body fat in obese mice, alongside a rise in beta-3 adrenergic receptor expression [2].

How it might work. The obvious guess was the beta-3 adrenergic receptor, the main lipolytic receptor on fat cells, whose expression both growth hormone and AOD-9604 restore in obese mice. But in beta-3 knockout mice, chronic treatment no longer reduced weight or increased lipolysis, while an acute dose still raised energy expenditure and fat oxidation — so the effect is not exerted directly through that receptor [2]. A parallel study in Zucker fatty rats mapped the same molecular and cellular actions on lipid metabolism [5]. An earlier study found the fragment altered glucose transport in rat fat cells [6], and the closely related C-terminal sequences have a hyperglycemic action of their own [7].

Human evidence. There is none in the published literature. The only human material ever exposed to it in these papers is isolated adipose tissue, in which AOD-9401 increased lipolysis and decreased lipogenesis in a dish [1]. AOD-9604 was taken into commercial development for obesity by Metabolic Pharmaceuticals and appears in mid-2000s reviews of obesity drugs in clinical development [8], but no trial results were published, and the program did not produce an approved drug. A 2026 review of peptides used for physique purposes lists it among compounds with no supporting human trial data [9].

It has since been tried for cartilage: injected into the knee joints of rabbits with induced osteoarthritis, alone or with hyaluronic acid, it improved cartilage scores and shortened lameness [10]. Again, rabbits.

The rationale is separation of function. The growth-promoting effects of growth hormone run through the growth hormone receptor and IGF-1; the effects on fat were mapped to a distinct C-terminal domain, residues 177-191 [3]. A peptide of that domain should therefore act on fat without the growth signaling that makes growth hormone itself unattractive as a weight-loss drug.

What the domain does to a fat cell. The 1993 study that defined it found the fragment antilipogenic to the same degree as the intact hormone, and specifically found no significant lipolytic effect, measured as glycerol release from rat epididymal fat pads [3]. Later work filled in the enzymology: AOD-9401 stimulated hormone-sensitive lipase, inhibited acetyl-CoA carboxylase and reproduced growth hormone's effect on diacylglycerol release in adipocytes [5]. The fragment also reduced both basal and insulin-stimulated glucose uptake in adipocytes from obese Zucker rats, and at equal concentrations it did so more strongly than intact growth hormone [6]. So "lipolytic" is a later gloss on a domain first characterized as antilipogenic, and the two assays do not agree.

The receptor. The obvious candidate was the beta-3 adrenergic receptor, the main lipolytic receptor on fat cells, whose suppressed expression in obese mice both growth hormone and AOD9604 restore to lean-mouse levels. But in beta-3 knockout mice, chronic treatment no longer reduced weight or raised lipolysis, while an acute dose still increased energy expenditure and fat oxidation - so the effect is not exerted directly through that receptor, even though raising its expression may contribute [2]. After three decades no binding site has been identified that explains the effect. Without a receptor and without human data, the mechanism remains a description of what happens in rodent fat rather than an explanation.

AOD9604 is the C-terminal fragment of human growth hormone, residues 177-191, with an additional tyrosine at the N terminus [11]; the same fragment is numbered 176-191 under the other convention, and it carries the disulfide-closed loop of the parent hormone [3]. It has been given by mouth and by injection in animals [1]. Doping control detects it in urine down to 50 pg/mL, and of the six metabolites formed when it is incubated in serum and urine, the nonapeptide CRSVEGSCG is far more stable than either the others or the parent, which widens the detection window [11][12].

There is no published human safety data for AOD-9604 — no trial, no pharmacokinetics, no adverse event reporting. The animal studies report no toxicity, but they were not designed as safety studies [1][2].

One thing worth noting from the older literature: synthetic peptides related to growth hormone's C-terminal sequence have a hyperglycemic action of their own in animals [7], and the fragment changes glucose transport in rat fat cells [6]. Whether that matters in people is unknown, because nobody has looked. What the chronic rodent work does show is that the fragment's effect on body weight and lipolysis depends on the beta-3 adrenergic receptor: 14 days of intraperitoneal AOD-9604 reduced body weight and fat in obese mice and raised beta-3 receptor expression, and the weight and lipolysis effects disappeared in beta-3 knockout mice, although energy expenditure and fat oxidation still rose acutely in them [2].