Altered Metabolism of Growth Hormone Receptor Mutant Mice: A Combined NMR Metabonomics and Microarray Study

Abstract

BackgroundGrowth 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.Methodology/Principal FindingsThe 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/SignificanceThe 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 β-oxidation.

1H NMR-based metabolomic analysis for identifying serum biomarkers to evaluate methotrexate treatment in patients with early rheumatoid arthritis

“…Increased levels of hypoxanthine in the serum of the effective group may be attributed to a decrease in the levels of oxidative stress following MTX therapy. Taurine is also known to have antioxidant effects which appear to downregulate pro-inflammatory cytokine production, and was present at increased levels in the effective group (28). Furthermore, the Krebs cycle is also likely to play an important role in the course of treatment since the concentrations of α-oxoglutarate and aspartate were decreased in the effective group when compared with those of the non-effective group (29,30).…”

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“…For example, metabolomics could explain how altered STAT5 signalling as a result of truncated intracellular domains of growth hormone receptor in liver tissue leads to lateonset obesity, as systemic metabolite changes were consistent with globally altered metabolism contributing to obesity 264 . A similar approach was used for data obtained from a human prostate cancer xenograft model in mice measured by NMR-based metabonomics and proteomics (two dimensional difference gel electrophoresis).…”

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“…However, other types of biological fluids such as amniotic fluid, seminal fluid, bile, cerebrospinal fluid (CSF) and gastric juices have also been analysed in metabonomic studies (Jordan and Cheng, 2007;Lindon et al, 2000;Romero et al, 2005;Wikoff et al, 2008). Furthermore, metabolic profiling of tissue biopsies is possible using high-resolution magic angle spinning (HR-MAS) NMR spectroscopy, displaying the flexibility of the technique (Mortishire- Smith et al, 2004;Schirra et al, 2008;Wu et al, 2006). …”

“…The versatility of metabonomics makes it an ideal tool for investigating animal models of obesity or the biochemical changes in obese individuals (Schirra et al, 2008). The progression of a disease can be monitored through the changes in metabolism of tissues or biofluids of an animal or individual.…”

“…A recent metabonomic study was performed in GH-deficient mice where the intracellular domain of the growth hormone receptor was truncated, impairing STAT5 signalling (Schirra et al, 2008). These mice became obese due to resulting metabolic changes arising from severe GH deficiency.…”