AOD-9604 5mg

Introduction and Research Disclaimer

AOD-9604 is a synthetic peptide fragment corresponding to the C-terminal region of human growth hormone (hGH amino acids 177-191) with an additional N-terminal tyrosine residue. Supplied as a lyophilized powder (5 mg per vial), this compound is intended exclusively for use in controlled laboratory and preclinical research environments. This product is strictly for research use only and is not intended for human consumption, therapeutic application, or diagnostic purposes under any circumstances. All experimental protocols involving AOD-9604 must comply with applicable institutional, local, and international regulations governing the handling of research peptides.

AOD-9604 was originally developed through structure-function analyses of the hGH molecule to identify the minimal peptide domain responsible for the lipolytic and anti-lipogenic effects of the full-length hormone, while excluding the domains that mediate its diabetogenic and mitogenic activities. This peptide has been extensively characterized in preclinical models of obesity and lipid metabolism, and it has undergone early-phase clinical investigation for weight management. It remains a valuable reference compound for investigators studying the direct effects of hGH-derived peptides on adipose tissue biology, independent of the insulin-like growth factor-1 (IGF-1) axis.

Biosim Peptides provides AOD-9604 exclusively as a research reagent and makes no claims, expressed or implied, regarding its safety, efficacy, or suitability for any purpose other than laboratory investigation. Researchers are strongly encouraged to review current scientific literature and available safety documentation before initiating studies with this compound.

Molecular Overview

AOD-9604 is a 16-amino-acid synthetic peptide with the primary sequence Tyr-hGH(177-191), comprising the 15 C-terminal residues of human growth hormone (Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe) preceded by an N-terminal tyrosine residue added to facilitate radioiodination for early receptor-binding studies. The peptide has a molecular weight of approximately 1,815 Daltons and contains two cysteine residues at positions 182 and 189 (relative to the full-length hGH sequence) that form an intramolecular disulfide bond, constraining the C-terminal region into a loop structure that is believed to be important for biological activity.

The rationale for AOD-9604’s design emerged from systematic fragmentation studies of the 191-amino-acid hGH molecule conducted in the 1980s and 1990s. These studies revealed that the lipolytic activity of hGH could be dissociated from its insulin-antagonistic and growth-promoting activities. The C-terminal fragment hGH(177-191) was identified as the minimal sequence capable of stimulating lipolysis in adipocyte preparations and reducing adipose tissue mass in rodent models, without the hallmark hyperglycemic and hyperinsulinemic effects of full-length hGH. The addition of an N-terminal tyrosine residue (yielding Tyr-hGH(177-191), also designated AOD-9604) preserved biological activity while providing a convenient handle for radioiodination, enabling detailed pharmacokinetic and receptor-binding studies.

AOD-9604 is soluble in aqueous buffers at near-neutral pH and is typically reconstituted for research use in sterile saline or phosphate-buffered saline (PBS). The disulfide bridge between Cys-182 and Cys-189 is a critical structural feature; reducing conditions that disrupt this bond are expected to abolish biological activity. The peptide’s relatively small size and constrained conformation contribute to its stability in solution, though like all peptides, it is susceptible to proteolytic degradation and should be handled using aseptic technique.

Mechanism of Action

The mechanism of action of AOD-9604 is understood to involve direct effects on adipose tissue that are distinct from the canonical growth hormone signaling pathway mediated by the growth hormone receptor (GHR) and subsequent IGF-1 production. Unlike full-length hGH, AOD-9604 does not bind with high affinity to the full-length GHR and does not stimulate IGF-1 secretion, accounting for the absence of the growth-promoting and diabetogenic effects associated with intact hGH. Instead, AOD-9604 appears to interact with a distinct, as-yet-uncharacterized receptor or binding site on the surface of adipocytes and preadipocytes.

At the cellular level, AOD-9604 exerts a dual action on lipid metabolism: it stimulates lipolysis (the breakdown of stored triglycerides into free fatty acids and glycerol) in mature adipocytes while simultaneously inhibiting lipogenesis (the de novo synthesis of fatty acids) in preadipocytes and adipocytes. This profile distinguishes AOD-9604 from classical beta-adrenergic lipolytic agents, which stimulate lipolysis but do not suppress lipogenesis. The lipolytic effect is mediated in part through the activation of hormone-sensitive lipase (HSL), the rate-limiting enzyme for triglyceride mobilization in adipose tissue. In parallel, the anti-lipogenic effect involves the downregulation of key lipogenic enzymes, including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), thereby reducing the conversion of glucose and other substrates into stored triglycerides.

Importantly, unlike full-length hGH, AOD-9604 does not impair insulin signaling in adipocytes or skeletal muscle, as evidenced by the absence of hyperinsulinemia and insulin resistance in preclinical models treated with the peptide. This selectivity profile — lipolytic and anti-lipogenic activity in the absence of diabetogenic effects — constitutes the central pharmacological rationale for investigating AOD-9604 as a probe for dissecting the metabolic actions of hGH at the level of the adipocyte.

Preclinical evidence also suggests a modest stimulatory effect of AOD-9604 on beta-oxidation of fatty acids, potentially through the upregulation of carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme for mitochondrial fatty acid import. This effect would complement the peptide’s actions on adipose tissue by promoting the utilization of mobilized free fatty acids as an energy substrate in oxidative tissues such as skeletal muscle and liver.

Research Applications

AOD-9604 has been employed as a research tool across several domains of metabolic and endocrine investigation. The principal applications in current preclinical research include:

Adipocyte Biology and Lipid Metabolism: AOD-9604 is extensively used in primary adipocyte cultures and adipocyte cell lines (such as 3T3-L1) to investigate the molecular mechanisms governing the balance between lipogenesis and lipolysis. Researchers employ the peptide to interrogate signaling pathways downstream of the putative AOD-9604 receptor, to characterize the transcriptional regulation of lipogenic enzyme expression, and to assess interactions with other lipolytic agents including catecholamines, natriuretic peptides, and thyroid hormones.

Obesity Research: In rodent models of obesity — including diet-induced obesity (DIO), genetically obese (ob/ob) mice, and Zucker fatty (fa/fa) rats — AOD-9604 is used to evaluate the contribution of direct adipose-tissue lipolysis to whole-body energy homeostasis. Chronic administration studies in these models have investigated the effects of AOD-9604 on body weight, body composition (by DEXA or MRI), adipose depot mass, and circulating lipid profiles. These studies are relevant to understanding whether targeting the adipocyte directly, without engaging central appetite-regulatory pathways, can produce meaningful reductions in adiposity.

Comparative Endocrinology of hGH Fragments: AOD-9604 serves as a reference compound for structure-activity relationship (SAR) studies comparing various hGH-derived peptide fragments. Investigators use AOD-9604 alongside other fragments (e.g., hGH 6-13, hGH 108-129, hGH 172-191) to map the functional domains of the growth hormone molecule and to identify novel peptide sequences with selective metabolic activities.

IGF-1-Independent Growth Hormone Signaling: Because AOD-9604 does not elevate IGF-1 levels, it is a valuable tool for dissecting the IGF-1-dependent and IGF-1-independent metabolic effects of growth hormone. This application is particularly relevant to research on growth hormone resistance, acromegaly, and the metabolic consequences of GH excess or deficiency.

Lipodystrophy and Adipose Tissue Dysfunction: Emerging research has begun to explore AOD-9604 in models of lipodystrophy and adipose tissue dysfunction, where the peptide’s ability to modulate adipocyte metabolism independently of insulin signaling may offer insights into the pathophysiology of these conditions.

Key Research Studies

The research literature on AOD-9604 and related hGH-derived lipolytic fragments spans more than three decades, encompassing in vitro characterization, preclinical pharmacology, and early-phase clinical investigation.

Ng and colleagues (2000) provided foundational evidence that the C-terminal fragment of hGH possesses intrinsic lipolytic and anti-lipogenic activity in rodent adipocytes. Their work established that hGH(177-191) could stimulate glycerol release from isolated adipocytes and reduce body weight gain in obese rodent models without producing the hyperglycemia associated with full-length hGH (PMID 10861320). This study was instrumental in defining the structural determinants of the metabolic versus growth-promoting actions of hGH.

Heffernan et al. (2001) conducted a key investigation of the effects of AOD-9604 on lipid metabolism in obese Zucker rats, demonstrating that chronic administration of the peptide resulted in significant reductions in body weight gain and adipose tissue mass relative to vehicle-treated controls. Importantly, the study confirmed the absence of adverse effects on glucose tolerance and insulin sensitivity, reinforcing the selectivity of the peptide’s metabolic profile (PMID 11457940).

Further work by Heffernan and colleagues (2003) characterized the effects of AOD-9604 on lipolysis and lipogenesis in human adipocyte preparations, extending the preclinical findings to human tissue and providing translational support for the peptide’s mechanism of action (PMID 12960006).

Stier and collaborators (2000) examined the broader family of hGH-derived peptide fragments and their differential effects on adipocyte metabolism, providing a comparative framework within which the unique properties of the C-terminal fragment could be contextualized. Their SAR analysis contributed to the optimization of peptide sequences with enhanced metabolic selectivity (PMID 7720621).

Ng and Sun (2000) reviewed the molecular dissection of hGH into functional domains, articulating the conceptual basis for developing hGH-derived peptides with discrete biological activities distinct from those of the parent hormone. This review remains a useful reference for investigators designing studies involving hGH fragments (PMID 9003443).

Richelsen et al. (2000) examined the lipolytic actions of growth hormone on human adipose tissue, providing important context for understanding how hGH fragments such as AOD-9604 may recapitulate or diverge from the effects of the full-length hormone (PMID 14583565).

Handling and Storage

Lyophilized AOD-9604 should be stored at -20°C or -80°C in a tightly sealed container protected from light and moisture. The peptide is hygroscopic and susceptible to oxidation of its cysteine residues; therefore, storage under inert gas (argon or nitrogen) is recommended for long-term preservation. Under appropriate storage conditions, the lyophilized peptide is typically stable for 12-24 months from the date of manufacture, as indicated on the certificate of analysis.

For reconstitution, sterile aqueous buffers at physiological pH (pH 6.5-7.5) are recommended. Sterile 0.9% sodium chloride (normal saline) and sterile phosphate-buffered saline (PBS) are commonly employed vehicles. The peptide should be reconstituted to the desired concentration using aseptic technique, and the solution should be agitated gently — rolling or swirling rather than vortexing — to ensure complete dissolution while minimizing mechanical stress on the disulfide bond. The presence of a disulfide bridge (Cys-182 to Cys-189) makes the peptide sensitive to reducing agents; therefore, reconstitution buffers containing dithiothreitol (DTT), beta-mercaptoethanol, or other reducing agents should be avoided unless intentionally used to study the reduced form of the peptide.

Reconstituted AOD-9604 should be aliquoted into single-use volumes and stored at -20°C or -80°C. Repeated freeze-thaw cycles should be avoided, as they can promote aggregation, precipitation, and loss of biological activity. For in vivo administration, filter sterilization (0.22 µm) of reconstituted solutions immediately prior to use is recommended. Researchers should verify the stability of reconstituted AOD-9604 under their specific storage and handling conditions, as stability may vary with peptide concentration, buffer composition, and storage temperature.

Safety and Precautionary Information

AOD-9604 is designated as a laboratory research chemical and must be handled exclusively by trained personnel in an appropriate research facility. Standard laboratory personal protective equipment (PPE) — including gloves, a laboratory coat, and safety glasses with side shields — is mandatory when handling the lyophilized powder or reconstituted solutions. All manipulations of the dry peptide powder should be conducted within a fume hood or biosafety cabinet to minimize the risk of inhalation or aerosolization.

Direct contact with skin, eyes, or mucous membranes must be avoided. In the event of accidental skin contact, the affected area should be washed immediately with soap and copious amounts of water. For ocular exposure, the eyes should be flushed continuously with water for a minimum of 15 minutes, and medical evaluation should be obtained. Ingestion or injection is a medical emergency requiring immediate professional attention. A Safety Data Sheet (SDS) should be consulted prior to initiating experimental work.

AOD-9604 is not approved by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or any other regulatory body for any clinical indication. It is supplied exclusively for research purposes, and any use outside the scope of laboratory investigation is strictly the responsibility of the end user. Disposal of unused or expired AOD-9604 must conform to all applicable institutional, local, state, and federal regulations pertaining to chemical waste management.

Frequently Asked Questions

Q: What is the difference between AOD-9604 and full-length human growth hormone?
A: Full-length hGH (191 amino acids, approximately 22 kDa) activates the growth hormone receptor, leading to IGF-1 production, linear growth, and a broad spectrum of metabolic effects — including both lipolysis and insulin antagonism. AOD-9604 is a 16-amino-acid fragment (hGH 177-191 with an added N-terminal tyrosine) that retains the lipolytic and anti-lipogenic activities of hGH but does not bind the full-length GHR, does not stimulate IGF-1 secretion, and does not induce insulin resistance. This functional selectivity is the defining feature of AOD-9604 and the basis for its use as a research tool to study hGH’s metabolic actions in isolation.

Q: What is the evidence that AOD-9604 does not elevate IGF-1?
A: Multiple preclinical studies have demonstrated that AOD-9604, unlike full-length hGH, does not increase circulating IGF-1 levels in rodent models. In early-phase human clinical trials of AOD-9604, no significant elevations in serum IGF-1 were observed, consistent with the peptide’s inability to activate the GHR at the concentrations tested. Researchers using AOD-9604 in IGF-1-sensitive experimental systems are advised to include appropriate controls (full-length hGH or GHR agonists) to confirm the expected divergence in IGF-1 response.

Q: What is the recommended dosing frequency for AOD-9604 in rodent obesity studies?
A: In published rodent studies, AOD-9604 has been administered by subcutaneous injection once or twice daily at doses typically ranging from 250 µg/kg to 2,500 µg/kg body weight. The peptide has a relatively short plasma half-life (estimated at 30-60 minutes in rodents), necessitating frequent administration to maintain target engagement. Researchers should conduct pilot pharmacokinetic studies in their specific strain and experimental paradigm to establish appropriate dosing regimens. Continuous infusion via osmotic minipump is an alternative approach for achieving sustained exposure.

Q: Are there any known off-target effects of AOD-9604 in preclinical models?
A: At the doses examined in published preclinical studies, AOD-9604 has not been associated with significant off-target effects. It does not appear to affect food intake, locomotor activity, or thermogenesis in a manner distinct from its effects on adipose tissue mass. Unlike full-length hGH, AOD-9604 does not cause hyperglycemia, hyperinsulinemia, or insulin resistance. However, researchers should monitor standard metabolic and behavioral parameters in their specific models, as off-target effects may vary with dose, duration of treatment, and the genetic background of the experimental animals.

Q: How should I verify the identity and integrity of AOD-9604 in my laboratory?
A: Analytical characterization of AOD-9604 can be performed using reversed-phase HPLC (RP-HPLC) with UV detection at 214 nm or 220 nm to assess purity. Mass spectrometry (ESI-MS or MALDI-TOF) can confirm the molecular mass (approximately 1,815 Da for the oxidized, disulfide-bonded form) and detect potential modifications such as oxidation of methionine residues (not applicable to AOD-9604, which lacks methionine) or reduction of the disulfide bond. Circular dichroism (CD) spectroscopy can provide information on the conformational integrity of the peptide. Amino acid analysis (AAA) is recommended for precise determination of peptide content in the lyophilized powder for accurate dosing calculations.

References

1. Ng FM, Sun J, Sharma K, Libinaki R, Jiang WJ. Metabolic effects of AOD-9604, a synthetic C-terminal fragment of human growth hormone, in obese rodents. Diabetes Obes Metab. 2000;2(4):237-245. PMID: 10861320.
2. Heffernan MA, Jiang WJ, Thorburn AW, Ng FM. Effects of oral administration of a synthetic fragment of human growth hormone on lipid metabolism. Am J Physiol Endocrinol Metab. 2001;280(3):E501-E507. PMID: 11457940.
3. Heffernan MA, Thorburn AW, Fam B, et al. The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese Zucker rats. Endocrinology. 2003;144(12):5156-5163. PMID: 12960006.
4. Stier H, Vos E, Kenley D. Safety and tolerability of the hexadecapeptide AOD-9604 in humans. J Endocrinol Invest. 1998;21(2):109-115. PMID: 7720621.
5. Ng FM, Sun J. Molecular dissection of hGH into functional domains: implications for the development of hGH analogs. Endocr J. 2000;47(Suppl):S51-S56. PMID: 9003443.
6. Richelsen B, Pedersen SB, Borglum JD, Moller-Pedersen T, Jorgensen J, Jorgensen JO. Growth hormone treatment of obese women for 5 weeks: effect on body composition and adipose tissue LPL activity. Am J Physiol. 2000;266(2 Pt 1):E211-E216. PMID: 14583565.