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The Effects of Human GH and Its Lipolytic Fragment (AOD9604) on Lipid Metabolism Following Chronic Treatment in Obese Mice and ß₃-AR Knock-Out Mice

Department of Biochemistry and Molecular Biology (M.H., E.O., R.G., W.J.J., F.M.N.) and Department of Pharmacology (R.J.S.), Monash University, Clayton, Australia 3800; and Department of Medicine (A.T.), University of Melbourne, Parkville, Australia 3052

Address all correspondence and requests for reprints to: A/Prof. Frank Ng, Department of Biochemistry and Molecular Biology (13d), Monash University, Clayton, Victoria 3800, Australia. E-mail: frank.ng{at}med.monash.edu.au

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 ß-adrenergic pathway, particularly with the ß₃-adrenergic receptors (ß₃-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 ß₃-AR RNA, the major lipolytic receptor found in fat cells. Importantly, both hGH and AOD9604 are capable of increasing the repressed levels of ß₃-AR RNA in obese mice to levels comparable with those in lean mice. The importance of ß₃-AR was verified when long-term treatment with hGH and AOD9604 in ß₃-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 ß₃-AR knock-out mice. In conclusion, this study demonstrates that the lipolytic actions of both hGH and AOD9604 are not mediated directly through the ß₃-AR although both compounds increase ß₃-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.

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