Adiponectin Deregulation in Systemic Autoimmune Rheumatic Diseases

Abstract

Deregulation of adiponectin is found in systemic autoimmune rheumatic diseases (SARDs). Its expression is downregulated by various inflammatory mediators, but paradoxically, elevated serum levels are present in SARDs with high inflammatory components, such as rheumatoid arthritis and systemic lupus erythematosus. Circulating adiponectin is positively associated with radiographic progression in rheumatoid arthritis as well as with cardiovascular risks and lupus nephritis in systemic lupus erythematosus. However, in SARDs with less prominent inflammation, such as systemic sclerosis, adiponectin levels are low and correlate negatively with disease activity. Regulators of adiponectin gene expression (PPAR-γ, Id3, ATF3, and SIRT1) and inflammatory cytokines (interleukin 6 and tumor necrosis factor α) are differentially expressed in SARDs and could therefore influence total adiponectin levels. In addition, anti-inflammatory therapy could also have an impact, as tocilizumab treatment is associated with increased serum adiponectin. However, anti-tumor necrosis factor α treatment does not seem to affect its levels. Our review provides an overview of studies on adiponectin levels in the bloodstream and other biological samples from SARD patients and presents some possible explanations why adiponectin is deregulated in the context of therapy and gene regulation.

Keywords: PPAR-γ; adiponectin; gene regulation; interleukin 6; systemic autoimmune rheumatic diseases; therapy; tumor necrosis factor α.

Figure 1

Gene expression of adiponectin—ADIPOQ (ENSG00000181092.9) in human tissues from the Genotype-Tissue Expression (GTEx) portal. The expression values are given in transcripts per million (log10 (TPM + 1)), calculated from a gene model with isoforms collapsed to a single gene. No other normalization steps were applied. Box plots are shown as median and as 25th and 75th percentile. Only tissues with the median TPM > 0.1 are presented.

Figure 2

(a) Adiponectin structure and isoforms. (b) Simplified adiponectin downstream signaling. ACC: Acetyl-CoA carboxylase, AMPK: AMP-activated protein kinase, APPL1: adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1, eNOS: Endothelial NOS, NF-Κb: Nuclear factor-κB, p38MAPK: p38 mitogen-activated protein kinase, PPAR-α: Peroxisome proliferator-activated receptor α, S1P: sphingosine-1-phosphate.

Figure 3

Adiponectin circulating levels observed in certain SARDs. The values are presented as standard mean difference (SMD) with 95% confidence intervals (CI) and association p values. The most recent meta-analysis with the highest number of studies included was presented for each SARD. AS: Ankylosing spondylitis, HC: Healthy controls, RA: Rheumatoid arthritis, SLE: Systemic lupus erythematosus, SSc: Systemic sclerosis.

Figure 4

Local loss of dWAT in SSc skin in addition to adipocytes undergoing AMT causes decreased adiponectin secretion. Consequently, its inhibitory effects on myofibroblasts are lost, which results in fibrosis. AMT: adipocyte mesenchymal transition, dWAT: dermal white adipose tissue, EMC: Extracellular matrix, SSc: Systemic sclerosis.

Figure 5

Superposition of trimeric globular domain of adiponectin (PDB: 6U66) in blue and TNF-α (PDB:1TNF) in yellow shows high 3D-structure similarity.

Figure 6

Simplified ADIPOQ gene regulation with TNF-α and IL-6. ATF3: Activating Transcription Factor 3, C-EBP: CCAAT-enhancer-binding protein, Erk1/2: extracellular signal-regulated kinases 1/2 FoxO1: Forkhead box protein O1, Id3: Inhibitor Of DNA Binding 3, IL: Interleukin, JAK: Janus kinase, JNK: Jun N-terminal kinase, NFAT: Nuclear factor of activated T-cells, PPAR-γ: Peroxisome-proliferator-activated receptor gamma, PPRE: Peroxisome proliferator response element, R: receptor, SIRT: Sirtuin, SREBP: Sterol regulatory element-binding protein, STAT: signal transducer and activator of transcription, TNF: Tumor necrosis factor.

Figure 7

Summary of adiponectin levels in SARDs associated with clinical manifestations, treatment and adiponectin gene regulation. AS: Ankylosing spondylitis, ATF3: Activating Transcription Factor 3, C-EBP: CCAAT-enhancer binding protein, CY: Cyclophosphamide, DMARD: Disease-modifying antirheumatic drugs, FoxO1: Forkhead box protein O1, GC: Glucocorticoids, Id3: Inhibitor Of DNA Binding 3, IL: Interleukin, JAK: Janus kinase, NFAT: Nuclear factor of activated T-cells, PBMCs: Peripheral blood mononuclear cells, PPRE: Peroxisome proliferator response element, RA: rheumatoid arthritis, SIRT: Sirtuin 1/NAD-dependent deacetylase, SLE: Systemic lupus, erythematosus, SREBP: Sterol regulatory element-binding protein, SSc: Systemic sclerosis, TCZ: Tocilizumab, TNF: Tumor necrosis factor.