The adipose tissue-specific proteome

The adipose tissue transcriptome

Transcriptome analysis of the adipose tissue can be visualized with regard to specificity and distribution of transcribed mRNA molecules (Figure 1). Specificity illustrates the number of genes with elevated or non-elevated expression in the adipose tissue compared to other tissues. Elevated expression includes three subcategory types of elevated expression:

• Tissue enriched: At least four-fold higher mRNA level in adipose tissue compared to any other tissues.
• Group enriched: At least four-fold higher average mRNA level in a group of 2-5 tissues compared to any other tissue.
• Tissue enhanced: At least four-fold higher mRNA level in adipose tissue compared to the average level in all other tissues.

Distribution, on the other hand, visualizes how many genes that have, or do not have, detectable levels (NX≥1) of transcribed mRNA molecules in the adipose tissue compared to other tissues. As evident in Table 1, all genes elevated in adipose tissue are categorized as:

• Detected in single: Detected in a single tissue
• Detected in some: Detected in more than one but less than one third of tissues
• Detected in many: Detected in at least a third but not all tissues
• Detected in all: Detected in all tissues

Figure 1. (A) The distribution of all genes across the five categories based on transcript specificity in adipose tissue as well as in all other tissues. (B) The distribution of all genes across the six categories, based on transcript detection (NX≥1) in adipose tissue as well as in all other tissues.

As shown in Figure 1, 212 genes show some level of elevated expression in the adipose tissue compared to other tissues. The three categories of genes with elevated expression in adipose tissue compared to other organs are shown in Table 1. In Table 2, the 2 enriched genes are defined.

Table 1. Number of genes in the subdivided categories of elevated expression in adipose tissue.

Table 2. The 2 genes with enriched expression in adipose tissue. "Tissue distribution" describes the transcript detection (NX≥1) in adipose tissue as well as in all other tissues. "mRNA (tissue)" shows the transcript level in adipose tissue as NX values. "Tissue specificity score (TS)" corresponds to the fold-change between the expression level in adipose tissue and the tissue with second highest expression level.

Protein expression of genes elevated in adipose tissue

In-depth analysis of the elevated genes in adipose tissue using antibody-based protein profiling allowed us to visualize the expression patterns of these proteins within the adipose tissue, including the location of several plasma proteins, enzymes and transporters.

Proteins specifically expressed in adipose tissue

Adipose tissue is mainly formed by adipocytes (fat cells) but also consists of pre-adipocytes, fibroblasts, blood vessels and inflammatory cells. It is a specialized loose connective tissue with a number of functions including storage of energy, protection of organs and secretion of hormones.

Examples of proteins expressed in the adipose tissue include FABP4, involved in lipid transport, LIPE, hydrolyze the stored triglycerides to free fatty acids, and PLIN1 and PLIN4, which have major roles in lipid droplet formation.

FABP4
LIPE

PLIN1
PLIN4

Plasma proteins

Plasma proteins are found in the blood plasma where red and white blood cells, and platelets are suspended. Plasma proteins play a key role in the coagulation of blood, defense mechanisms of the body, transport of various substances and regulation of different functions within the human body. Abnormal levels of plasma proteins can lead to the progression of various diseases. Hence, the levels of plasma proteins in the blood are widely used to gather information about the health and disease status of an individual.

Adipose tissue was at first characterized as a connective tissue that contained lipid droplets, without a link to the metabolism of the organism. After the discovery of adipose-derived serum factors, adipose tissue is now regarded as an endocrine organ at the center of energy homeostasis. 49 plasma proteins are identified in the adipose tissue elevated gene lists.

Examples of plasma proteins with elevated expression in adipose tissue include LEP, which plays a major role in the regulation of body weight by decreasing food intake and increasing energy expenditure, and ADIPOQ, which is involved in modulating several of metabolic processes including glucose regulation and lipid oxidation.

LEP
ADIPOQ

Enzymes

Enzymes, speed up all vital biological processes, catalyze biochemical reactions and enable the building of chemical substances that make up the main components of the human body including proteins, carbohydrates and fats. These proteins require additional entities, coenzymes, for functional activity. Coenzymes are typically small molecules that accept or donate functional groups to assist in the enzymatic reaction.

An example of an enzyme with elevated expression in adipose tissue is LIPE, a hormone-sensitive lipase that in adipose tissue primarily hydrolyzes stored triglycerides to free fatty acids.

LIPE

Transporters

The majority of biological solutes are charged organic or inorganic molecules and hydrophobic cellular membranes establish concentration gradients through the use of transporters. Transporters carry solutes across cell membranes and the energy required for these active transport processes is obtained from the cell ATP turnover.

One of the largest families of membrane proteins in the human genome is the solute carrier (SLC) family. Members of the SLC superfamily are present in a large number of the cells and allow the transport of nutrients, amino acids, lipid structures, nucleosides, nucleotides, as well as diverse metabolites, both on the cell surface and on intracellular organelles.

An example of a transporter with elevated expression in adipose tissue is HAS1.

HAS1

Gene expression shared between adipose tissue and other tissues

There are 50 group enriched genes expressed in adipose tissue. Group enriched genes are defined as genes showing a 4-fold higher average level of mRNA expression in a group of 2-5 tissues, including adipose tissue, compared to all other tissues.

In order to illustrate the relation of adipose tissue tissue to other tissue types, a network plot was generated, displaying the number of genes with shared expression between different tissue types.

Figure 2. An interactive network plot of the adipose tissue enriched and group enriched genes connected to their respective enriched tissues (grey circles). Red nodes represent the number of adipose tissue enriched genes and orange nodes represent the number of genes that are group enriched. The sizes of the red and orange nodes are related to the number of genes displayed within the node. Each node is clickable and results in a list of all enriched genes connected to the highlighted edges. The network is limited to group enriched genes in combinations of up to 3 tissues, but the resulting lists show the complete set of group enriched genes in the particular tissue.

The adipose tissue shares expression of a few genes with several other tissue types but has the most shared group enriched gene expression with breast.

An example of group enriched gene expression shared between adipose tissue and liver is ADH1B, a member of the alcohol dehydrogenase family which plays a major role in ethanol catabolism.

ADH1B - liver
ADH1B - soft tissue

Adipose tissue function

Adipose tissue is a highly specialized loose connective tissue and has a number of physiological functions including the storage of energy and secretion of hormones such as leptin. Protection of the organs in the body as well as insulation are other important features. Fat is located all over the human body but mainly around organs (visceral fat) and beneath the skin (subcutaneous). The adipose tissue is mainly formed by adipocytes but also consists of pre-adipocytes, fibroblasts, blood vessels and inflammatory cells. There are different types of adipose tissue including white adipose tissue (WAT) and brown adipose tissue (BAT). WAT has a major role in the progression of obesity and its adverse outcomes. Obesity has become a global pandemic and it is considered as one of the greatest threats to human health. Obesity is also associated with one or more comorbidities, including type 2-diabetes, cardiovascular disease and increased risk of cancer. BAT is in contrast to WAT, thermogenic, a property induced by uncoupling protein 1 (UCP1), which is located in the inner mitochondrial membrane. UCP1 enables BAT to release energy as heat by uncoupling mitochondrial respiration.

Adipose tissue histology

Adipocytes are the main cell type in adipose tissue. Adipose tissue is typically homogeneous and finely divided by faint septa. Adipose tissue is spread throughout the body and surrounds most organs and tissues in the human body. In the skin, underlying adipose tissue forms the subcutaneous layer as an integral component of the skin. Microscopically adipose tissue is mainly composed of indistinct lobules of adipocytes surrounded by thin bands of collagen and small blood vessels. The cytoplasm of the adipocyte is compressed at the perimeter of the cell as it is displaced by a single lipid vacuole and only a thin rim of the cell membrane is evident in the microscopic image. Adipocytes contain a small, thin and oval nucleus located peripheral to the dominating lipid vacuole, whereas nuclei of capillary endothelial cells are present at intersections between multiple adipocytes.

The histology of human adipose tissue including detailed images and information can be viewed in the Protein Atlas Histology Dictionary.

Background

Here, the protein-coding genes expressed in adipose tissue are described and characterized, together with examples of immunohistochemically stained tissue sections that visualize corresponding protein expression patterns of genes with elevated expression in adipose tissue.

Transcript profiling was based on a combination of three transcriptomics datasets (HPA, GTEx and FANTOM5), corresponding to a total of 9332 samples from 113 different human normal tissue types. The final consensus normalized expression (NX) value for each tissue type was used for classification of all genes according to the tissue specific expression into two different categories, based on specificity or distribution.

Relevant links and publications

Uhlén M et al., Tissue-based map of the human proteome. Science (2015)
PubMed: 25613900 DOI: 10.1126/science.1260419

Yu NY et al., Complementing tissue characterization by integrating transcriptome profiling from the Human Protein Atlas and from the FANTOM5 consortium. Nucleic Acids Res. (2015)
PubMed: 26117540 DOI: 10.1093/nar/gkv608

Fagerberg L et al., Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. (2014)
PubMed: 24309898 DOI: 10.1074/mcp.M113.035600

Mardinoglu A et al., Defining the Human Adipose Tissue Proteome To Reveal Metabolic Alterations in Obesity. J Proteome Res. (2014)
PubMed: 25219818 DOI: 10.1021/pr500586e

Histology dictionary - adipocytes in soft tissue