Defining the Human Adipose Tissue Proteome To Reveal Metabolic Alterations in Obesity

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.