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

Both human GH (hGH) and a lipolytic fragment (AOD9604) synthesized from its C-terminus are capable of inducing weight loss and increasing lipolytic se nsitivity following longterm treatment in mice. One mechanism by which this may occur is through an interaction with the beta -adrenergic pathway, par ticularly with the beta (3)-adrenergic receptors (beta (3)-AR). Here we des cribe 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 lipolyti c receptor found In fat cells. Importantly, both hGH and AOD9604 are capabl e of increasing the repressed levels of beta (3)-AR RNA in obese mice to le vels 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 lipol ysis that was observed in wild-type control mice. However, in an acute expe riment, AOD9604 was capable of increasing energy expenditure and fat oxidat ion in the beta (3)-AR knock-out mice. In conclusion, this study demonstrat es that the lipolytic actions of both hGH and AOD9604 are not mediated dire ctly through the beta (3)-AR although both compounds increase beta (3)-AR e xpression, which may subsequently contribute to enhanced lipolytic sensitiv ity.