GC−MS Metabolomic Analysis Reveals Significant Alterations in Cerebellar Metabolic Physiology in a Mouse Model of Adult Onset Hypothyroidism

Abstract

Although adult-onset hypothyroidism (AOH) has been connected to neural activity alterations, including movement, behavioral, and mental dysfunctions, the underlying changes in brain metabolic physiology have not been investigated in a systemic and systematic way. The current knowledge remains fragmented, referring to different experimental setups and recovered from various brain regions. In this study, we developed and applied a gas chromatography-mass spectrometry (GC-MS) metabolomics protocol to obtain a holistic view of the cerebellar metabolic physiology in a Balb/cJ mouse model of prolonged adult-onset hypothyroidism induced by a 64-day treatment with 1% potassium perchlorate in the drinking water of the animals. The high-throughput analysis enabled the correlation between multiple parallel-occurring metabolic phenomena; some have been previously related to AOH, while others implicated new pathways, designating new directions for further research. Specifically, an overall decline in the metabolic activity of the hypothyroid compared to the euthyroid cerebellum was observed, characteristically manifested in energy metabolism, glutamate/glutamine metabolism, osmolytic/antioxidant capacity, and protein/lipid synthesis. These alterations provide strong evidence that the mammalian cerebellum is metabolically responsive to AOH. In light of the cerebellum core functions and its increasingly recognized role in neurocognition, these findings further support the known phenotypic manifestations of AOH into movement and cognitive dysfunctions.

Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice

“…In the present study we investigated the effect of a chemically induced model of adult onset hypothyroidism on behavioral parameters (fear/ anxiety and learning/memory) and on the activity of two isoforms of the AChE in five specific brain regions of male mice. In our experimental set-up, adult onset hypothyroidism was effectively performed as indicated by the decreased body weight gain of hypothyroid mice at the end of KClO 4 treatment, in accordance to our previous findings [45] and the literature [17,47,48]. In addition, our biochemical studies were performed in the same animals used for the OF and EPM tasks as mentioned in Materials and methods.…”

“…Statistically, euthyroid animals gain weight to a percentage of 56% as to their initial BW measurement while the respective percentage for hypothyroid group is 9.1%. The decreased rate of growth of animals represents an index of the induction of hypothyroidism that has been previously evaluated with regard to its effects on brain metabolism [45].…”

Plasma proteome and metabolome characterization of an experimental human thyrotoxicosis model

“…3). Threonate, which is either derived from glycated proteins or represents a degradation product of ascorbate [103], was previously linked to altered thyroid function in two murine models [45, 104], but not yet in humans.…”

Metabolic Profiling Provides a System Understanding of Hypothyroidism in Rats and Its Application

“…Maria Klapa's group [33] applied metabolomic method to delineate significant alterations in cerebellar metabolic physiology related to hypothyroidism. However, little is known about the overall changes of urinary metabolites in an organism with hypothyroidism.…”