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 animal study investigated how human growth hormone (hGH) and a synthetic lipolytic fragment derived from its C-terminus, AOD9604, affect fat metabolism and body weight in obese and genetically modified mice. Obese mice received 14 days of chronic intraperitoneal administration of either compound. Both hGH and AOD9604 reduced body weight and body fat in obese mice, and these effects were associated with increased expression of beta-3 adrenergic receptor (β3-AR) RNA — a key receptor involved in fat breakdown — bringing levels in obese mice closer to those seen in lean mice. To test whether β3-AR was essential to these effects, the researchers used β3-AR knock-out mice; in these animals, chronic treatment with either compound failed to produce the body weight reduction or increased lipolysis seen in normal mice. However, in an acute experiment, AOD9604 still increased energy expenditure and fat oxidation in knock-out mice, suggesting additional mechanisms exist. The authors concluded that while neither compound acts directly through β3-AR, both upregulate its expression, which may amplify lipolytic sensitivity over time. Key limitations include the exclusively animal-based design and the use of intraperitoneal administration, limiting direct translation to humans.
Why this grade: All experiments were conducted in mouse models (obese and β3-AR knock-out mice) with no human subjects, providing no direct human evidence for the effects of AOD9604 or hGH on lipid metabolism.
Both human GH (hGH) and a lipolytic fragment (AOD9604) synthesized from its C-terminus are capable of inducing weight loss and increasing lipolytic sensitivity following long-term treatment in mice. One mechanism by which this may occur is through an interaction with the beta-adrenergic pathway, particularly with the beta(3)-adrenergic receptors (beta(3)-AR). Here we describe how hGH and AOD9604 can reduce body weight and body fat in obese mice following 14 d of chronic ip administration. These results correlate with increases in the level of expression of beta(3)-AR RNA, the major lipolytic receptor found in fat cells. Importantly, both hGH and AOD9604 are capable of increasing the repressed levels of beta(3)-AR RNA in obese mice to levels comparable with those in lean mice. The importance of beta(3)-AR was verified when long-term treatment with hGH and AOD9604 in beta(3)-AR knock-out mice failed to produce the change in body weight and increase in lipolysis that was observed in wild-type control mice. However, in an acute experiment, AOD9604 was capable of increasing energy expenditure and fat oxidation in the beta(3)-AR knock-out mice. In conclusion, this study demonstrates that the lipolytic actions of both hGH and AOD9604 are not mediated directly through the beta(3)-AR although both compounds increase beta(3)-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.
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