Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment

This study was one of the first to demonstrate that the C-terminal fragment of human growth hormone (amino acids 176-191, also known as AOD9604) possesses independent lipolytic activity when administered chronically in an animal model of obesity. Obese ob/ob mice received daily treatment with full-length hGH, the HGH 176-191 fragment, or vehicle for several weeks.

The results demonstrated that both hGH and its C-terminal fragment:

• Significantly reduced body weight gain compared to the control group
• Increased fat oxidation in vivo, measured by indirect calorimetry
• Elevated plasma glycerol levels, an indicator of active lipolysis in adipose tissue

Crucially, the HGH 176-191 fragment showed metabolic advantages over full-length hGH: it did not cause hyperglycemia nor reduce insulin secretion — adverse effects frequently associated with chronic growth hormone use. This dissociation between lipolytic and diabetogenic effects is clinically relevant.

The researchers proposed that the 176-191 fragment contains the minimal domain necessary for GH lipolytic activity but lacks the domains responsible for GH receptor activation and its growth-promoting and diabetogenic effects. This study laid the groundwork for the development of AOD9604 as a potential anti-obesity agent with a favorable metabolic profile, an approach that represented an innovative concept in peptide pharmacology.