What is AOD-9604?

AOD-9604 is a synthetic 16-amino-acid peptide derived from the C-terminal fragment (residues 177-191) of human growth hormone (hGH), with an additional tyrosine at the N-terminus for stability. Its sequence is Tyr-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe, with a molecular weight of approximately 1815.1 g/mol. AOD-9604 is a water-soluble, lipolytic peptide designed to target fat metabolism, featuring a disulfide bond between two cysteine residues for structural stability. It is typically administered via subcutaneous injection (e.g., 300-500 mcg/day) or oral formulations in research settings. Developed initially by Metabolic Pharmaceuticals as an anti-obesity drug, AOD-9604 is under investigation for weight loss and related metabolic conditions, available as a research chemical or through specialized protocols. Its development as a therapeutic was halted in 2007 after mixed clinical trial results, though research continues.

Mechanism of Action

AOD-9604’s primary mechanism involves stimulating fat breakdown and inhibiting fat formation, particularly in adipose tissue, through the following processes:

Lipolysis Stimulation: AOD-9604 enhances the breakdown of triglycerides in fat cells into glycerol and free fatty acids, likely by mimicking hGH’s lipolytic domain, though its exact receptor interaction remains unclear.

Lipogenesis Inhibition: It suppresses the transformation of non-fat materials (e.g., glucose) into stored fat, reducing adipocyte fat accumulation without affecting appetite or growth pathways.

Beta-3 Adrenergic Receptor Upregulation: In preclinical models, AOD-9604 increases β3-adrenergic receptor (β3-AR) expression in obese mice, enhancing lipolytic sensitivity, though this is not its sole mechanism as it retains activity in β3-AR knockout mice.

Energy Expenditure Increase: Acute studies suggest AOD-9604 boosts fat oxidation and energy expenditure, contributing to fat loss independently of β3-AR in some contexts.

No IGF-1 Stimulation: Unlike hGH, AOD-9604 does not increase insulin-like growth factor-1 (IGF-1) levels, avoiding growth-related or diabetogenic effects.

Metabolic Focus: Its actions are specific to fat metabolism, lacking hGH’s broader anabolic effects, making it a targeted candidate for obesity research.

AOD-9604’s specificity for fat reduction without affecting glucose or growth pathways distinguishes it from full-length hGH.

Benefits

AOD-9604’s benefits, supported by preclinical and limited clinical studies, include:

Fat Reduction: Promotes significant fat loss, particularly in visceral and abdominal areas, as shown in obese animal models and early human trials.

Weight Loss: Induces weight reduction without altering food intake or insulin sensitivity, offering a potential metabolic approach to obesity.

Metabolic Health: Improves lipid profiles (e.g., cholesterol) in some studies, supporting cardiovascular risk reduction.

Cartilage and Bone Support: Preliminary research suggests regenerative effects on cartilage and bone, potentially aiding osteoarthritis or injury recovery.

No Impact on Blood Sugar: Maintains glucose tolerance and insulin sensitivity, avoiding hGH’s diabetogenic risks.

Anti-Inflammatory Potential: May reduce inflammation in adipose tissue, though this is less studied.

These benefits highlight AOD-9604’s potential for fat-targeted therapies, though human efficacy remains under scrutiny.

Use Cases

AOD-9604 is primarily experimental, with applications including:

Obesity Management: Investigated for weight loss in obese populations (e.g., 1 mg/day orally in trials or 300 mcg/day SC in research), targeting fat reduction.

Metabolic Disorders: Explored for dyslipidemia and metabolic syndrome in preclinical models (e.g., 5 mg/kg in rodents).

Musculoskeletal Repair: Used in studies for cartilage regeneration (e.g., combined with hyaluronic acid in rabbits) and bone health.

Exercise Enhancement: Applied off-label to boost fat metabolism and recovery in athletic contexts (e.g., 300-500 mcg/day SC).

Aging and Wellness: Investigated for age-related fat accumulation and metabolic decline in preclinical settings.

Administration varies from daily subcutaneous injections to oral doses, with protocols tailored to research or off-label use.

Research Studies

Below is a summary of key studies on AOD-9604, focusing on its mechanisms and benefits:

Ng et al. (2000) - Hormone Research Showed AOD-9604 reduces body weight in obese Zucker rats (19 days, 500 µg/kg/day) by over 50% vs. placebo via lipolysis and fat oxidation.

Heffernan et al. (2001) - Endocrinology Demonstrated AOD-9604 (14 days, IP) reduces fat mass in obese mice, upregulating β3-AR, though it retains lipolytic effects in β3-AR knockouts.

Stier et al. (2013) - Journal of Endocrinology and Metabolism Found AOD-9604 (multiple trials, up to 1 mg/day oral) safe and tolerable in humans, with no IGF-1 increase or glucose impairment.

Phase 2B OPTIONS Trial (2006-2007) - Metabolic Pharmaceuticals Reported modest weight loss (1.8 kg vs. placebo over 12 weeks, 0.25-1 mg/day oral) in 536 subjects, but a 24-week follow-up showed insufficient efficacy, halting development.

Siejka et al. (2015) - Osteoarthritis and Cartilage Indicated AOD-9604 (4-7 weeks, with hyaluronic acid) reduces cartilage degeneration in rabbits, suggesting regenerative potential.

These studies reflect AOD-9604’s promise and limitations, with ongoing research refining its scope.

Considerations

Safety: Well-tolerated in trials, with mild side effects (e.g., headache, injection-site reactions); long-term data beyond 24 weeks are lacking.

Regulation: Not FDA-approved; available as a research chemical or via compounding pharmacies, with GRAS status for food use in some contexts.

Evidence: Strong preclinical support for lipolysis; human trials show modest weight loss, with efficacy debates prompting development cessation in 2007.

In conclusion, AOD-9604 is a synthetic peptide with potential to enhance fat metabolism and support weight loss, leveraging hGH’s lipolytic effects without its broader risks. While preclinical data are robust, human efficacy remains inconsistent, necessitating further research to validate its therapeutic role.

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