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.

Defining the Human Brain Proteome Using Transcriptomics and Antibody-Based Profiling with a Focus on the Cerebral Cortex

“…Genes expressed in the frontal cortex were classified according the categories determined to describe expression profiles in a large set of related and unrelated tissues [9,19–24]. In total 13,992 of all known genes are expressed (FPKM >1) in the frontal cortex (Fig 1D).…”

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity

“…However, studies by other researchers suggest that the decrease in AT BCAA catabolism does contribute significantly to circulating BCAA levels 37,38 and that the gene expression of the BCAA catabolism enzymes in obesity is downregulated in AT, but not in liver nor muscle. 39 Increased BCAA levels have not only been correlated with insulin resistance 36,[40][41][42] but also predict future risk of T2DM. 34,41 Here we show that, in what we assume as the more advanced stage of metabolic dysfunction in SAT, the decrease in BCAA catabolism pathways is more pronounced and associated with higher fasting insulin levels in the heavy co-twins.…”

Metrics for the Human Proteome Project 2015: Progress on the Human Proteome and Guidelines for High-Confidence Protein Identification

“…The tissues with the most mRNAs highly enriched (at least 5× the levels in all other tissues) are testis (999) and brain (318). Several tissue-specific HPA publications have been published, and more are expected during 2015 with tissue-specific immunohistochemical and transcript evidence to guide specimen selection for further MS studies, for example, describing the brain, 18 liver, 19 testis, 20 kidney, 21 pancreas, 22 skin, 23 adipose tissue, 24 gallbladder, 25 lung, 26 gastrointestinal tract, 27 and cardiac and skeletal muscle. 28 HPA, v14, will be released in Fall 2015 along with a novel Rodent Brain Atlas comprising immunofluorescently stained whole-mouse-brain sections.…”