title: Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes.
abstract: OBJECTIVE
  Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes-associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations.
  
  
  METHODS
  Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites.
  
  
  RESULTS
  Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5-anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state.
  
  
  CONCLUSIONS
  By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin.
authors.affiliation: Department of Nutritional Physiology, Technische Universität München, Gregor-Mendel-Str. 2, 85350, Freising, Germany, pieter.giesbertz@tum.de.
authors.forename: Pieter
authors.initials: P
authors.lastname: Giesbertz
authors.forename: Inken
authors.initials: I
authors.lastname: Padberg
authors.forename: Dietrich
authors.initials: D
authors.lastname: Rein
authors.forename: Josef
authors.initials: J
authors.lastname: Ecker
authors.forename: Anja S
authors.initials: AS
authors.lastname: Höfle
authors.forename: Britta
authors.initials: B
authors.lastname: Spanier
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005227:Fatty Acids / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D005786:Gene Expression Regulation; D006038:Glyoxylates / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction; D013012:Sorbitol / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D006038:Glyoxylates; D020738:Leptin; D019000:Phosphotyrosine; D013012:Sorbitol; C031150:glyoxylic acid; D008239:Lysine; D020155:3-Hydroxybutyric Acid