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Signatures of acylcarnitine and acyl‐CoA species suggest specific alterations of mitochondrial oxidation in mouse models of obesity and diabetes
Author(s) -
Daniel Hannelore,
Giesbertz Pieter,
Mueller Katrin,
Schomburg Dietmar
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1293.1
Subject(s) - medicine , endocrinology , insulin resistance , streptozotocin , diabetes mellitus , metabolite , chemistry , insulin , beta oxidation , fatty acid , fgf21 , metabolism , biology , biochemistry , receptor , fibroblast growth factor
Obesity, insulin resistance and diabetes are characterized by changes in circulating plasma metabolite markers derived from amino acid and fatty acid metabolism including acylcarnitines (AC). In identifying organs and pathways as origins of the changes in plasma metabolites, we determined AC profiles in plasma and tissues from mouse models representing different stages of obesity and diabetes development. The leptin‐deficient ob/ob mouse served as a model for obesity associated with insulin resistance but pancreas hypertrophy whereas the db/db mouse is obese, insulin resistant with severe hyperglycemia and eventually pancreatic failure. A streptozotocin‐induced insulin‐deficient mouse was employed as a model for type I diabetes or end‐point stage type II diabetes with extreme hyperglycemia and ketosis. We used a sensitive LC‐MS/MS method to quantify around 45 AC derived from fatty acid and amino acid oxidation pathways. We furthermore determined concentrations of odd‐numbered fatty acids for which the metabolic origin is largely unknown. Since AC are derived from the conversion of acyl‐CoA we additionally determined a number of corresponding acyl‐CoA species in liver and assessed how they correlate with AC levels. Results displayed strong increases in AC derived from branched‐chain amino acid degradation in plasma and tissues of all mouse models, but most pronounced in streptozotocin‐treated animals. All mice also displayed increased levels of odd‐numbered AC in liver while dicarboxylic‐acylcarnitines derived from omega‐oxidation were strongly decreased in ob/ob and db/db mice. Correlations between AC and acyl‐CoA concentrations in liver were strongest for monocarboxylic metabolites, while dicarboxylic acylcarnitines like malonylcarnitine and succinylcarnitine showed no or negative correlations with their respective acyl‐CoA species. In summary, our analysis revealed major alterations in specific pathways of mitochondrial fatty acid and amino acid oxidation in the different mouse models during diabetes progression.