Nina Varah MSc Thesis / BACKGROUND: Brown adipose tissue (BAT) has emerged as an attractive target to address the dramatic rise in obesity and non-alcoholic fatty liver disease (NAFLD) in adults and children due to its ability to clear lipids through thermogenesis when activated with cold stimulation. Cross-sectional studies have identified an inverse relationship between BAT and NAFLD in adults, although no linking mechanism or relevance in children is known. Metabolomics provides a non-invasive platform to investigate BAT physiology and its relationship with hepatic fat in an effort to identify potential targets for further investigation.
PROJECT OBJECTIVES:
1) To explore the associations between the plasma metabolome and BAT in adults and children.
2) To explore the associations between the plasma metabolome and hepatic fat in adults and children.
3) To identify metabolites associated with both BAT and hepatic fat as potential linking mechanisms for further study.
METHODOLOGY: We recruited 63 male and female adults aged 18 to 57 years and 25 healthy male children aged 8 to 10 years into this cross-sectional study. Study participants underwent blood work, body composition measurement (dual energy X-ray absorptiometry; DXA) and magnetic resonance imaging (MRI) - proton density fat fraction (PDFF) measurements of whole liver hepatic fat, pre- and post-cold supraclavicular fat. BAT activity was calculated as the percent change between post and pre-cold BAT PDFF with the cold stimulus consisting of a water-perfused suit maintained at 18°C for 3-hours (adult) or 1-hour (pediatric). Targeted liquid-chromatography/mass spectrometry metabolomics of 102 metabolites was conducted on fasted plasma and multivariate linear regression with multiple testing correction was used to examine metabolite predictors of BAT measures and hepatic fat.
RESULTS: In the adult cohort (n=63, median age 25.9 years, median body mass index (BMI) 25.4 kg/m2), five metabolites were associated with baseline BAT lipid content, where an elevated lipid content may indicate a whiter adipose tissue-like phenotype. Aconitate and creatine commonly predict increased baseline BAT lipid content (β=0.420, P=0.001 and β=0.408, P=0.001, respectively), and reduced BAT activity (β=-0.462, P=0.002 and (β=-0.402, P=0.002, respectively). Alanine and two acyl-carnitines also predicted reduced BAT activity. Glutamic acid was similarly related to higher baseline BAT (β=0.480, P<0.001) and hepatic lipid content independent of age and sex (β=0.392, P=0.002). Three other metabolites were directly related to hepatic fat, and serine inversely. In children (n=25, median age 9.89 years, mean BMI Z-score 1.25), cysteine and cystine were trending towards a significant relationship with higher baseline BAT lipid content, and were both related to elevated hepatic fat independent of adiposity (cysteine: quadratic β=-0.714, p<0.001 and cystine: quadratic β=0.592, p<0.001). Two hydroxy-proline isomers and L-carnitine were associated with reduced BAT activity.
CONCLUSION: In adults, several metabolites were associated with reduced BAT activity and with a higher baseline BAT lipid content in the non-stimulated state – aconitate and creatine were related to both. Acylcarnitines or their metabolites related to BAT in both children and adults, which may suggest areas for subsequent investigation of BAT metabolism. Glutamic acid in adults and cysteine and cystine in children were weakly related to elevated baseline BAT and hepatic fat content. Further, amino acids such as glutamic acid and cysteine may be markers of increased ectopic fat accumulation – and are also associated with a whiter ambient BAT phenotype. Cumulatively, these findings highlight targets for further investigation into BAT physiology and the link to the liver. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25508 |
| Date | January 2020 |
| Creators | Varah, Nina |
| Contributors | Morrison, Katherine, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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