The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice

This study investigated the lipolytic mechanisms of action of the HGH 176-191 fragment (designated AOD9604) compared to full-length human growth hormone (hGH), using obese ob/ob mice and beta(3)-adrenergic receptor knockout mice. The objective was to elucidate whether the lipolytic effects of the fragment are mediated by the GH receptor or through alternative mechanisms.

The results demonstrated that both AOD9604 and hGH significantly reduced body weight gain and increased lipolysis in obese mice when administered chronically. However, fundamental differences in the mechanism of action were identified:

• AOD9604 did not compete for the GH receptor in binding assays, indicating action through a distinct pathway
• The fragment did not induce cell proliferation in bioassays, unlike full-length hGH
• The lipolytic action of AOD9604 was not abolished in beta(3)-AR knockout mice, suggesting a mechanism independent of this adrenergic pathway

These findings are particularly relevant from a safety perspective, as full-length hGH, despite its lipolytic effects, is associated with cell proliferation, insulin resistance, and other adverse effects mediated by the GH receptor. AOD9604, by not interacting with this receptor, theoretically offers the metabolic benefits without the associated risks.

The authors concluded that the HGH 176-191 fragment retains the lipolytic properties of full-length growth hormone through a GH receptor-independent mechanism, with a potentially superior safety profile for applications in obesity treatment.