title: Defining the human adipose tissue proteome to reveal metabolic alterations in obesity.
abstract: White adipose tissue (WAT) has a major role in the progression of obesity. Here, we combined data from RNA-Seq and antibody-based immunohistochemistry to describe the normal physiology of human WAT obtained from three female subjects and explored WAT-specific genes by comparing WAT to 26 other major human tissues. Using the protein evidence in WAT, we validated the content of a genome-scale metabolic model for adipocytes. We employed this high-quality model for the analysis of subcutaneous adipose tissue (SAT) gene expression data obtained from subjects included in the Swedish Obese Subjects Sib Pair study to reveal molecular differences between lean and obese individuals. We integrated SAT gene expression and plasma metabolomics data, investigated the contribution of the metabolic differences in the mitochondria of SAT to the occurrence of obesity, and eventually identified cytosolic branched-chain amino acid (BCAA) transaminase 1 as a potential target that can be used for drug development. We observed decreased glutaminolysis and alterations in the BCAAs metabolism in SAT of obese subjects compared to lean subjects. We also provided mechanistic explanations for the changes in the plasma level of BCAAs, glutamate, pyruvate, and α-ketoglutarate in obese subjects. Finally, we validated a subset of our model-based predictions in 20 SAT samples obtained from 10 lean and 10 obese male and female subjects.
authors.affiliation: Department of Chemical and Biological Engineering, Chalmers University of Technology , 412 96 Gothenburg, Sweden.
authors.forename: Adil
authors.initials: A
authors.lastname: Mardinoglu
authors.forename: Caroline
authors.initials: C
authors.lastname: Kampf
authors.forename: Anna
authors.initials: A
authors.lastname: Asplund
authors.forename: Linn
authors.initials: L
authors.lastname: Fagerberg
authors.forename: Björn M
authors.initials: BM
authors.lastname: Hallström
authors.forename: Karolina
authors.initials: K
authors.lastname: Edlund
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Mathias
authors.initials: M
authors.lastname: Uhlen
authors.forename: Jens
authors.initials: J
authors.lastname: Nielsen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism; D000597:Amino Acids, Branched-Chain / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D056865:Ideal Body Weight; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000378:metabolism*; D050177:Overweight / Q000378:metabolism; D020543:Proteome / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D050151:Subcutaneous Fat / Q000378:metabolism / Q000502:physiology; D013548:Sweden; D000637:Transaminases / Q000378:metabolism
chemical_list: D000597:Amino Acids, Branched-Chain; D007656:Ketoglutaric Acids; D020543:Proteome; C490590:BCAT1 protein, human; D000637:Transaminases
keywords: adipocytes; genome-scale metabolic modeling; proteome; transcriptome; white adipose tissue