AOD-9604 (hGH Fragment 176-191)
AOD-9604 is the C-terminal fragment (residues 176–191) of human growth hormone, specifically the region responsible for GH's lipolytic (fat-burning) activity. It stimulates fat breakdown and inhibits fat synthesis through beta-3 adrenergic receptor activation in adipose tissue, without raising IGF-1 or producing GH's mitogenic effects — offering a targeted fat metabolism approach with a favorable safety profile. Grade B.
Overview
AOD-9604 was developed by Metabolic Pharmaceuticals (now Calzada Ltd, Australia) as a safer alternative to GH for obesity treatment. The compound isolates the lipolytic C-terminal fragment of GH (residues 176–191) by adding a tyrosine residue to enable cyclization, preserving the fat-metabolism activity while eliminating GH's IGF-1-stimulating and proliferative effects.
Phase II trials showed meaningful fat loss in obese subjects. Phase III trials (AOD-9604-02, -03 series) using oral formulations were completed but showed insufficient efficacy for regulatory approval (~3.4 kg additional fat loss over 24 weeks). Importantly, the compound received FDA GRAS (Generally Recognized as Safe) designation, which represents favorable regulatory acknowledgment of its safety profile.
In the research context, AOD-9604 is studied both for direct fat metabolism effects and for potential applications in osteoarthritis (cartilage regeneration data from Australian Phase II trials), making it an unusually broad-spectrum research compound for a GH fragment.
Mechanism of Action
AOD-9604's primary lipolytic mechanism involves activation of beta-3 adrenergic receptors (β3-AR) in white and brown adipose tissue. β3-AR activation triggers adenylyl cyclase → cAMP → PKA → hormone-sensitive lipase (HSL) phosphorylation cascade, releasing fatty acids from triglyceride stores (lipolysis). Simultaneously, AOD-9604 downregulates fatty acid synthase (FAS) expression, inhibiting de novo lipogenesis.
Unlike full GH, AOD-9604 does not bind the classical GH receptor (GHR) and therefore does not activate JAK2/STAT5 signaling responsible for IGF-1 induction, linear growth, and insulin resistance. This mechanistic specificity — β3-AR activation without GHR engagement — is the key feature distinguishing AOD-9604 from GH itself.
For osteoarthritis applications, AOD-9604 has shown chondroprotective effects in animal models: reducing cartilage degradation, promoting chondrocyte proliferation, and upregulating collagen type II synthesis — a separate mechanism from its fat metabolism effects, possibly mediated by local growth factor receptor interactions in articular tissue.
Research Protocol B
| Parameter | Standard | Notes |
|---|---|---|
| Dose | 300 mcg/day | Phase II data; some use 200–500 mcg |
| Frequency | Once daily | Morning fasted preferred |
| Route | SubQ | Abdominal injection |
| Timing | AM fasted | 30–60 min before food |
| Cycle Length | 8–12 weeks | Phase II: 24 weeks |
Reconstitution Quick-Calc
Side Effects & Safety
- Excellent safety profile — FDA GRAS designation achieved
- No IGF-1 elevation (key safety advantage over GH)
- No insulin resistance
- Injection site irritation (mild, common)
- Rare: headache, nausea
- No hormonal suppression
- No carpal tunnel, edema, or joint pain associated with GH excess
Clinical Evidence
Demonstrated AOD-9604 activates β3-AR in adipocytes to stimulate lipolysis and inhibit lipogenesis, without GHR binding or IGF-1 elevation. Established primary mechanism and safety basis.
Phase II randomized trial showing statistically significant fat mass reduction in obese adults at 1 mg/day oral dose over 12 weeks. No adverse effects on IGF-1, insulin, or glucose tolerance.
Intra-articular AOD-9604 in 140 patients with knee osteoarthritis. Demonstrated significant pain reduction and functional improvement at 6 months vs placebo, documenting a second clinical indication beyond fat metabolism.
Stacking Recommendations
| Stack Partner | Synergy |
|---|---|
| Semaglutide | GLP-1 appetite suppression + AOD-9604 direct lipolysis = complementary fat loss |
| Tesamorelin | GHRH-mediated GH pulse + AOD-9604 targeted lipolysis for body composition |
| MOTS-c | Mitochondrial metabolic activation + adipose-specific lipolysis |
Frequently Asked Questions
Explore More
GLP-1 weight management
FDA-approved GHRH / fat reduction
Mitochondrial metabolic peptide
Browse all 251 compounds
Build protocols
Precision dosing
