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 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.
Heffernan
M
M
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia 3800.
Summers
R J
RJ
Thorburn
A
A
Ogru
E
E
Gianello
R
R
Jiang
W J
WJ
Ng
F M
FM
D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D019382:Human Growth Hormone / Q000494:pharmacology*; D006801:Humans; D050356:Lipid Metabolism; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012016:Reference Values; D013004:Somatostatin / Q000494:pharmacology*; D013997:Time Factors
C441619:AOD 9604; D010446:Peptide Fragments; D012333:RNA, Messenger; D022702:Receptors, Adrenergic, beta-3; D019382:Human Growth Hormone; D013004:Somatostatin