Dataset Information

Strain-Specific Liver Metabolite Profiles in Medaka.

ABSTRACT: The relationship between genetic variation and phenotypic traits is often poorly understood since specific genotypes do not always easily translate into associated phenotypes, especially for complex disorders. The genetic background has been shown to affect metabolic pathways and thus contribute to variations in the metabolome. Here, we tested the suitability of NMR metabolomics for comparative analysis of fish lines as a first step towards phenotype-genotype association studies. The Japanese rice fish, medaka (Oryzias latipes), is a widely used genetic vertebrate model with several isogenic inbred laboratory strains. We used liver extracts of medaka iCab and HO5 strains as a paradigm to test the feasibility of distinguishing the metabolome of two different inbred strains. Fifteen metabolites could be detected in uni- and multivariate analyses that showed strain-specific levels. Differences could be assigned to specific metabolic pathways. Our results show that NMR spectroscopy is a suitable method to detect variance of the metabolome caused by subtle genetic differences. Thus, it has the potential to address genotype-phenotype associations in medaka, providing an additional level of phenotypic analysis.

SUBMITTER: Soergel H

PROVIDER: S-EPMC8617739 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Strain-Specific Liver Metabolite Profiles in Medaka.

Soergel Hannah H Loosli Felix F Muhle-Goll Claudia C

Metabolites 20211029 11

The relationship between genetic variation and phenotypic traits is often poorly understood since specific genotypes do not always easily translate into associated phenotypes, especially for complex disorders. The genetic background has been shown to affect metabolic pathways and thus contribute to variations in the metabolome. Here, we tested the suitability of NMR metabolomics for comparative analysis of fish lines as a first step towards phenotype-genotype association studies. The Japanese ri ...[more]

PMID: 34822402

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Project description:The HTT CAG expansion mutation causes Huntington's Disease and is associated with a wide range of cellular consequences, including altered metabolism. The mutant allele is expressed widely, in all tissues, but the striatum and cortex are especially vulnerable to its effects. To more fully understand this tissue-specificity, early in the disease process, we asked whether the metabolic impact of the mutant CAG expanded allele in heterozygous B6.HdhQ111/+ mice would be common across tissues, or whether tissues would have tissue-specific responses and whether such changes may be affected by diet. Specifically, we cross-sectionally examined steady state metabolite concentrations from a range of tissues (plasma, brown adipose tissue, cerebellum, striatum, liver, white adipose tissue), using an established liquid chromatography-mass spectrometry pipeline, from cohorts of 8 month old mutant and wild-type littermate mice that were fed one of two different high-fat diets. The differential response to diet highlighted a proportion of metabolites in all tissues, ranging from 3% (7/219) in the striatum to 12% (25/212) in white adipose tissue. By contrast, the mutant CAG-expanded allele primarily affected brain metabolites, with 14% (30/219) of metabolites significantly altered, compared to wild-type, in striatum and 11% (25/224) in the cerebellum. In general, diet and the CAG-expanded allele both elicited metabolite changes that were predominantly tissue-specific and non-overlapping, with evidence for mutation-by-diet interaction in peripheral tissues most affected by diet. Machine-learning approaches highlighted the accumulation of diverse lipid species as the most genotype-predictive metabolite changes in the striatum. Validation experiments in cell culture demonstrated that lipid accumulation was also a defining feature of mutant HdhQ111 striatal progenitor cells. Thus, metabolite-level responses to the CAG expansion mutation in vivo were tissue specific and most evident in brain, where the striatum featured signature accumulation of a set of lipids including sphingomyelin, phosphatidylcholine, cholesterol ester and triglyceride species. Importantly, in the presence of the CAG mutation, metabolite changes were unmasked in peripheral tissues by an interaction with dietary fat, implying that the design of studies to discover metabolic changes in HD mutation carriers should include metabolic perturbations.

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Project description:ContextThe associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood.ObjectiveWe aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content.Design, setting, and participantsWe measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%).ResultsWe replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine.ConclusionsBMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.

Dataset Information

Strain-Specific Liver Metabolite Profiles in Medaka.

Publications

Strain-Specific Liver Metabolite Profiles in Medaka.

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