AOD-9604

This study examined the mechanism of action of AOD-9604, a synthetic analogue of the hGH 177–191 fragment, in wild-type and β3-adrenergic receptor (β3-AR) knockout mice. In obese (ob/ob) mice, chronic administration of AOD-9604 was associated with reduced cumulative body-weight gain, increased lipolysis in isolated adipocytes, and upregulation of β3-AR mRNA expression in adipose tissue. The chronic weight-reducing and lipolytic responses were substantially attenuated in β3-AR knockout animals, supporting a β3-AR–dependent component of the fragment's metabolic activity. The authors concluded that the lipolytic action of the hGH C-terminal fragment is at least partly mediated through the β3-adrenergic pathway in adipocytes and does not require the canonical growth hormone receptor signaling responsible for IGF-1 elevation and insulin antagonism.

Scientists tested how a small piece of growth hormone called AOD-9604 affects fat cells in mice. They found that the peptide pushes fat cells to break down stored fat, and it appears to work by amplifying signals through a specific receptor on fat cells called the β3-adrenergic receptor — the same receptor that normally responds to adrenaline-like signals to mobilize energy. When the researchers tested the peptide in mice genetically engineered without that receptor, much of the fat-loss effect disappeared, suggesting the receptor is an important part of the pathway. Importantly, the peptide did not produce the blood-sugar or growth effects associated with full-length growth hormone.

This animal study investigated the lipid-metabolism effects of the synthetic hGH C-terminal fragment when administered orally to obese (ob/ob) mice. Researchers reported that oral administration was associated with reduced cumulative body-weight gain and reduced adipose tissue mass relative to untreated controls. In isolated adipocytes, the fragment was associated with stimulation of hormone-sensitive lipase activity and inhibition of acetyl-CoA carboxylase, consistent with simultaneous enhancement of lipolysis and suppression of lipogenesis. The data supported the hypothesis that the C-terminal lipolytic domain of hGH can be separated from the growth-promoting and diabetogenic actions of the full hormone, and that the isolated fragment retains metabolic activity on adipose tissue when delivered orally in a rodent model.

Researchers gave obese mice a small fragment of growth hormone by mouth and watched what happened to their body weight and fat tissue. The mice gained less weight and accumulated less fat compared with untreated mice. When the team looked inside fat cells, they saw two changes happening at once — the machinery that breaks fat down was more active, and the machinery that builds new fat was less active. The takeaway was that this short fragment kept the fat-related effects of growth hormone but left behind the blood-sugar and growth effects, which is why it was attractive as a candidate for further obesity research.