Altered metabolism of growth hormone receptor mutant mice: a combined NMR metabonomics and microarray study.
BACKGROUND
Growth hormone is an important regulator of post-natal growth and metabolism. We have investigated the metabolic consequences of altered growth hormone signalling in mutant mice that have truncations at position 569 and 391 of the intracellular domain of the growth hormone receptor, and thus exhibit either low (around 30% maximum) or no growth hormone-dependent STAT5 signalling respectively. These mutations result in altered liver metabolism, obesity and insulin resistance.


RESULTS
The analysis of metabolic changes was performed using microarray analysis of liver tissue and NMR metabonomics of urine and liver tissue. Data were analyzed using multivariate statistics and Gene Ontology tools. The metabolic profiles characteristic for each of the two mutant groups and wild-type mice were identified with NMR metabonomics. We found decreased urinary levels of taurine, citrate and 2-oxoglutarate, and increased levels of trimethylamine, creatine and creatinine when compared to wild-type mice. These results indicate significant changes in lipid and choline metabolism, and were coupled with increased fat deposition, leading to obesity. The microarray analysis identified changes in expression of metabolic enzymes correlating with alterations in metabolite concentration both in urine and liver. Similarity of mutant 569 to the wild-type was seen in young mice, but the pattern of metabolites shifted to that of the 391 mutant as the 569 mice became obese after six months age.


CONCLUSIONS
The metabonomic observations were consistent with the parallel analysis of gene expression and pathway mapping using microarray data, identifying metabolites and gene transcripts involved in hepatic metabolism, especially for taurine, choline and creatinine metabolism. The systems biology approach applied in this study provides a coherent picture of metabolic changes resulting from impaired STAT5 signalling by the growth hormone receptor, and supports a potentially important role for taurine in enhancing beta-oxidation.
Schirra
Horst Joachim
HJ
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. h.schirra@uq.edu.au
Anderson
Cameron G
CG
Wilson
William J
WJ
Kerr
Linda
L
Craik
David J
DJ
Waters
Michael J
MJ
Lichanska
Agnieszka M
AM
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008297:Male; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009765:Obesity / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011986:Receptors, Somatotropin / Q000235:genetics*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013654:Taurine / Q000378:metabolism
D011986:Receptors, Somatotropin; D050799:STAT5 Transcription Factor; D013654:Taurine