AOD9604 Potential for Fat Cell Breakdown in Adipocytes

AOD9604 is a 16-amino-acid peptide that comprises the C-terminal amino acid sequence (176–191) of human growth hormone (hGH). A tyrosine residue replaces the endogenous N-terminal alanine to facilitate receptor engagement.⁽¹⁾ Research has posited that this fragment encompasses GH’s primary lipolytic domain. The conserved disulfide bridge—analogous to Cys182–Cys189 in full-length hGH—potentially confers structural stability by locking the peptide into a bioactive conformation. This S–S linkage, together with the added N-terminal tyrosine, may support resistance to acidic gastric pH and proteolytic enzymes, thereby supporting oral bioavailability.

Definitive receptor targets remain under investigation. That said, AOD9604 is believed to emulate hGH’s fat-burning potential on targets like hormone-sensitive lipase (HSL) and acetyl-CoA carboxylase (ACC) without significantly altering carbohydrate metabolism or stimulating IGF-1 production. Some research data suggests it may also interact with alternate pathways—for example, via β₃-adrenergic receptors—to support breakdown of fat cells further while potentially avoiding the mitogenic and glycemic risks associated with intact hGH.⁽²⁾

 

Research

Potential Interactions of AOD9604 with Fat Breakdown

AOD9604 may partly reproduce the fat-breakdown potential of full-length hGH. It is proposed that adipocytes exposed to AOD9604 may trigger an increase in intracellular cAMP. This increase in cAMP may activate protein kinase A (PKA), which then appears to phosphorylate hormone-sensitive lipase (HSL) on specific serine sites. Once phosphorylated, HSL appears to expose more hydrophobic regions. This supports HSL’s movement from the cytosol onto lipid droplets, at which point it is believed to interact with triglyceride stores.

Since HSL is the enzyme that is said to support fat cell breakdown by breaking down stored triglycerides into free fatty acids and glycerol, its activation may lead to a reduction in fat cell size. This is suggested by in vitro work by Ng et al. using fat cells collected from murine models exposed to a truncated version of AOD9604 that contains the (177–191) amino acids. This version is believed to boost HSL’s catalytic activity in a concentration-dependent manner.⁽³⁾ When the researchers running the study measured the release of fatty acids and glycerol from radiolabeled triglycerides, they observed about a 40–50% increase compared to the starting levels. These interactions in laboratory settings are thought to contribute to an increase in HSL activity.

Further research by Ng et al., specifically on AOD9604, observed a notable increase in glycerol levels.⁽⁴⁾ The experiment in question involved obese murine models, and the scientists commented that there was “a 23% increase in glycerol release from adipose tissue” within the murine models. Notably, both trials suggest that the increase in markers of HSL activation and fat cell breakdown occurs within minutes of exposure to the peptide. Thus, the research suggests that AOD9604 may support faster fat cell breakdown in the short term by activating the cAMP–PKA–HSL pathway, similar to hGH.

Potential Interactions of AOD9604 with Fat Store Accumulation

Another potential mechanism related to fat cells, which may be common between AOD9604 and hGH, is the apparent mitigation of acetyl-CoA carboxylase (ACC), an enzyme involved in fatty acid synthesis, thus potentially limiting new adipose tissue accumulation. Thus, AOD9604 may also slow down the formation of new fat cells. The publication by Ng et al. in obese murine models exposed to the peptide for approximately three weeks suggested that any gain in overall mass was estimated to be cut in half compared to placebo controls. This potential result coincides with signs of both increased fat breakdown and reduced fat accumulation.⁽⁴⁾

The same tissue samples from the models under observation exhibited lower ACC activity, indicating a reduced conversion of acetyl-CoA into malonyl-CoA, the first committed step in fatty acid synthesis. With less malonyl-CoA available, it becomes more difficult to form new fat cells. On top of this, an enzyme called carnitine palmitoyltransferase-1 (CPT-1) is freed from additional inhibition, potentially shuttling more fatty acids into mitochondria for burning rather than storage. Notably, AOD9604 also appears to interact with HSL and ACC, but does not support carbohydrate metabolism or insulin sensitivity. This is in contrast to the potential of hGH in this regard.

Potential Interactions of AOD9604 with Adrenergic Receptors

Further research on the topic suggests that prolonged experimentation protocols with AOD9604 may prime fat cells for supported fat breakdown by interacting with the adrenergic system, particularly the β₃-adrenergic receptors (β₃-AR), which serve as the primary lipolytic switches in fat cells. Research by Hefferman et al. using obese murine models suggests that these models may exhibit a downregulation of β₃-adrenergic receptors (β₃-AR). In turn, downregulation of these receptors may blunt lipolytic sensitivity in murine obesity.⁽⁵⁾

The exposure of research models to AOD9604 has been suggested to restore β₃-AR mRNA levels to those observed in lean controls. When coinciding with marked reductions in both white and brown adipose tissue depots. These researchers propose that without β₃-AR, neither AOD9604 nor full-length hGH may sustain the same decline in overall mass or increase in glycerol release observed in the murine models. This suggests that upregulating β₃-AR may be a crucial factor in how AOD9604 adequately supports fat cell breakdown over prolonged laboratory protocols.

Overall Potential of AOD9604 on Fat Cell Oxidation

Overall, the research suggests that AOD9604 may have a surprisingly broad relevance to fat metabolism. The aforementioned laboratory data indicate that exposure to the peptide may lead to increases in fat breakdown by more than 20% alongside significant reductions in the synthesis of new fat. Consequently, Ng et al. observed that this may limit gains in fat stores in obese murine models by over 50% ⁽⁴⁾. This limitation of fat cell gain may also be due to the suggestions by Heffernan et al. that AOD9604 may “re-sensitize” adipose tissue to adrenergic signals. This occurs through an increase in β₃-adrenergic receptor expression in obese murine models.

These changes were associated with marked and sustainable boosts in fatty acid oxidation, with suggested increases of up to 216% in murine models of obesity.⁽⁵⁾ Taken together, these observations suggest that AOD9604 may act through multiple coordinated mechanisms to support fat metabolism, especially in obesity-related laboratory scenarios robustly.

Depot-Specific Potential of AOD9604 on Fat Cell Mobilization

Research by Dehkhoda et al. has observed that “GH relevant adipose tissue in a depot-specific manner and relevant other features of adipose tissue (for example, senescence, adipocyte subpopulations, and fibrosis), all of which [may] relevant lipolysis.”⁽⁶⁾ It’s conceivable that, much like full-length hGH, AOD9604 might also not act uniformly across all types of adipocytes, but instead may have “preferred” targets. Specifically, visceral fat cells and brown fat cells are richer in β₃-adrenergic receptors and hormone-sensitive lipase, while subcutaneous white fat cells tend toward higher acetyl-CoA carboxylase expression.

By upregulating β₃-AR and supporting HSL phosphorylation, AOD9604 is therefore thought to support a more robust lipolytic response in visceral adipocytes where those receptors and enzymes are most abundant. This is believed to lead to quicker triglyceride hydrolysis and glycerol release. Similarly, brown adipose cells, already primed for thermogenesis, might respond to AOD9604 with a pronounced spike in energy expenditure.

In theory, direct PKA-driven activation of uncoupling proteins may accelerate mitochondrial fat oxidation. This may contribute to the shrinking of brown depots or even encourage the “beiging” of nearby white fat cells. In contrast, subcutaneous stores, having lower baseline receptor and enzyme levels, might exhibit a milder—but still measurable—decline in triglyceride content. This reduction may be observed primarily through the peptide’s concurrent ACC mitigation, which relieves the CPT-1 blockade. Therefore, researchers may expect different results with AOD9604 experimentation, depending on the type of fat cells employed.

You can find AOD 9604 for sale with 99% purity, on our website (available for research use only).

NOTE: These products are intended for laboratory research use only. This peptide is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.

 

References:

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2. Cox HD, Smeal SJ, Hughes CM, Cox JE, Eichner D. Detection and in vitro metabolism of AOD9604. Drug Test Anal. 2015 Jan;7(1):31-8. doi: 10.1002/dta.1715. Epub 2014 Sep 10. PMID: 25208511.
3. Ng FM, Jiang WJ, Gianello R, Pitt S, Roupas P. Molecular and cellular actions of a structural domain of human growth hormone (AOD9401) on lipid metabolism in Zucker fatty rats. J Mol Endocrinol. 2000 Dec;25(3):287-98. doi: 10.1677/jme.0.0250287. PMID: 11116208.
4. Ng FM, Sun J, Sharma L, Libinaka R, Jiang WJ, Gianello R. Metabolic studies of a synthetic lipolytic domain (AOD9604) of human growth hormone. Horm Res. 2000;53(6):274-8. doi: 10.1159/000053183. PMID: 11146367.
5. Heffernan MA, Thorburn AW, Fam B, Summers R, Conway-Campbell B, Waters MJ, Ng FM. Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment. Int J Obes Relat Metab Disord. 2001 Oct;25(10):1442-9. doi: 10.1038/sj.ijo.0801740. PMID: 11673763.
6. Dehkhoda F, Lee CMM, Medina J, Brooks AJ. The Growth Hormone Receptor: Mechanism of Receptor Activation, Cell Signaling, and Physiological Aspects. Front Endocrinol (Lausanne). 2018 Feb 13;9:35. doi: 10.3389/fendo.2018.00035. PMID: 29487568; PMCID: PMC5816795.