AOD-9604: Mechanism of Action

The mechanism of action of AOD9604 centers on the regulation of lipid metabolism through a signaling cascade that is distinct from the growth-promoting pathways activated by full-length hGH. The key pathways are:

1. Beta-3 Adrenergic Receptor (β3-AR) Activation

In murine adipose tissue, the lipolytic effects of AOD9604 are critically dependent on functional beta-3 adrenergic receptors (β3-AR). Studies using β3-AR knockout mice demonstrated a complete abolition of AOD9604-induced lipolysis, confirming the receptor as an essential mediator [1]. In obese (ob/ob) mice, chronic research application with AOD9604 at 500 µg/kg/day i.p. for 14 days resulted in significant upregulation of β3-AR mRNA expression in white adipose tissue, effectively restoring lipolytic sensitivity that is typically blunted in the obese phenotype [1][10].

2. cAMP / Hormone-Sensitive Lipase (HSL) Pathway

Activation of β3-AR by AOD9604 stimulates adenylate cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP) levels. Elevated cAMP activates protein kinase A (PKA), which phosphorylates hormone-sensitive lipase (HSL), the rate-limiting enzyme in triglyceride hydrolysis. This cascade promotes the breakdown of stored triglycerides into free fatty acids and glycerol (lipolysis) [2][11].

3. Inhibition of Acetyl-CoA Carboxylase (ACC) / Anti-Lipogenesis

Concurrently, AOD9604 inhibits acetyl-CoA carboxylase (ACC), the enzyme that catalyzes the first committed step in de novo fatty acid synthesis (lipogenesis). By suppressing ACC activity, AOD9604 reduces the conversion of acetyl-CoA to malonyl-CoA, thereby inhibiting new fat formation [2][12]. This dual action—stimulating fat breakdown while inhibiting fat synthesis—accounts for the net reduction in adipose tissue mass observed in preclinical models.

4. Why AOD9604 Does NOT Activate IGF-1 or the hGH Receptor

A critical distinction of AOD9604 from full-length hGH is its inability to activate the growth hormone receptor (GHR). Full-length hGH binds two GHR molecules (receptor dimerization), triggering the JAK2/STAT5 signaling cascade that stimulates hepatic production of Insulin-like Growth Factor 1 (IGF-1) [13]. Because AOD9604 represents only the C-terminal tail of hGH (residues 177–191), it lacks the structural domains (helices A and B) required for high-affinity GHR binding and dimerization [8][14]. Consequently, AOD9604 does not:

• Elevate serum IGF-1 levels [3][15]
• Stimulate cell proliferation (no mitogenic activity) [8]
• Induce insulin resistance or hyperglycemia [2][16]

This selectivity for metabolic effects without growth-promoting reported observations in study populations was a key design objective in the development of AOD9604 [3].