Metabolomics and Metabolic Network Analysis in Brain Research: Investigating the effect of adult-onset-hypothyroidism in a mouse model

Maria Klapa, Institute of Chemical Engineering Sciences, Foundation for Research & Technology-Hellas, Patras, Greece
Catherine Vasilopoulou, Institute Of Chemical Engineering Sciences, Foundation For Research & Technology-hellas, Patras, Greece
Marigoula Margarity, Department Of Biology, University Of Patras, Patras, Greece

Systems biology through high-throughput biomolecular analyses enabled neuroscientists to move from the study of individual molecules or circuits to a systems-level perspective of brain physiology. Regarding the brain metabolic activity in particular, the vast majority of neurophysiology studies to-date focus on the investigation of few “biomarker” molecules in specific brain region(s) being considered more relevant to the investigated dysfunctions and mainly in male animals. Thus, there is a need for systemic and systematic investigations of brain metabolic physiology taking into consideration the brain regional variation and the differences between sexes. With this work, we support the significance of carrying out holistic analysis of the brain metabolic dynamics using metabolomics and metabolic network analysis in the context of a mouse model of adult onset hypothyroidism (AOH). Our current knowledge about the AOH effect on the metabolic physiology of mammalian brain remains fragmented, derived from various brain regions and experimental setups. In this study, we acquired the gas chromatography-mass spectrometry (GC-MS) metabolic profiles of five brain regions in both male and female Balb-c/J mice after a two-month treatment with 1% KClO4 in their drinking water starting on the 60th postnatal day. We analyzed 735 metabolic profiles in total, corresponding to 245 biological samples. Multivariate statistical analysis indicated that the main discriminatory factor between samples is the brain regional variation. Cortex, cerebellum and midbrain rely mainly on glucose-centric metabolism, while hippocampus and striatum on lipid-centric. Moreover, AOH affects the brain metabolic physiology in a region-specific and sex-dependent manner, confirming the need for these differences to be considered in the experimental design and result interpretation of relevant brain studies.