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Adiponectin Signaling Pathway

Figure1. Adiponectin signaling pathway.

Overview of Adiponectin

Among the biologically active proteins secreted by fat cells, adiponectin is one of the most abundant protein products expressed by adipose tissue genes and is abundantly present in the blood circulation. It appears in circulating plasma in the human body at a concentration of 3-30 ug/ml. Adiponectin is also known as Acrp30, Apm1, AdipoQ, and GBP28. Initially, adiponectin was found in human subcutaneous adipose tissue, plasma, and murine fat cells. As an insulin hypersensitizing hormone (An Insulin-sensitizing Hormone), adiponectin can increase the fatty acid oxidation and sugar absorption of skeletal muscle cells, significantly enhance insulin's inhibition of gluconeogenesis and inhibit liver glycogen production. It is an important regulator of the body's lipid metabolism and regulation of blood glucose homeostasis. The nuclear transcription factor NF-κB is an important factor involved in the transcriptional regulation of VCAM-1, ICAM-1, and selectin-E by TNF-α. Ouchi and Kihara et al reported that adiponectin may regulate endothelial cell function by inhibiting the signaling pathway of NF-κB. NF-κB-inducible kinase (NIK) phosphorylates the IKB kinase (IKK) complex and activates NF-κB. TNF receptor binding factor 2 is a junction protein of NIK and TNF-α signaling pathway, which is a bifurcation point for TNF-α-induced NIK-NF-κB activation and activation of JNK or p38 pathway, and NIK is not involved in the activation of JNK and p38 kinase. Vascular smooth muscle proliferation induced by platelet-derived growth factor (PDGF) or heparin-binding epidermal growth factor (HB-EGF) plays an important role in vascular disease, while the physiological concentration of adiponectin is vascular smooth muscle induced by PDGF-BB with important inhibitory effects on proliferation and migration. In addition, adiponectin can inhibit the production and release of TNF with a certain anti-inflammatory effect, and an important cytoprotective effect on alcoholic liver injury.

Adiponectin family

Adiponectin is a novel protein secreted by adipocytes, containing 244 amino acids. Primary sequence analysis suggests that it contains four functional regions: the signal peptide of the first 18 amino acids, and the amino-terminal non-helical function of 23 amino acids, a segment of 22 collagen repeats (including 8 fully repeating Gly-X-Pro and 14 incomplete repeats of Gly-XY) and a carboxy-terminal carboxy-terminal end, which may be involved in the formation of a carboxy-terminal spherical functional domain. It has been found that the endogenous adiponectin produced by adipocytes is post-translationally modified into 8 isomers, 6 of which are glycosyl isomers, and the glycosylation sites are in 68, 71, 80 and 1044 Lys residues of the collagen-like functional regions. Wang et al. found that the glycosylation of the four Lys residues plays a key role in maintaining insulin sensitization. When Arg is used instead of glycosylated Lys, insulin sensitization is greatly attenuated. Since Yukio et al. from the University of Otsuka Medical Research Institute of Japan first isolated the fat-rich gene transcript 1/ablipin cDNA library from human plasma in 1996, a lot of research on apM1 has made us have a clearer understanding. Three clones containing apM1, two lambada clones, and one BAC clone have been discovered. apM1, a gene encoding adiponectin, is located on human chromosome 3q27 and has a length of 16 kb, including three exons ranging in size from 18 bp to 4277 bp, and two introns of 0.8 and 12 kb, respectively. The regulatory sequence of the apM1 gene contains a putative promoter element rather than a classical TATA box. The third exon of the gene has a longer 3' untranslated sequence, including three Alu repeats. This exon-intron of the apM1 gene is very similar to the ob gene encoding leptin.

Adiponectin signaling pathway

  1. Adiponectin signaling pathway cascade
    The greatest role of adiponectin is to regulate lipid metabolism. Low adiponectin is closely related to obesity, cardiovascular disease and T2DM and other insulin resistance or high insulin status, to some extent as an evaluation of obesity or T2DM insulin resistance index. There is no clear conclusion on the mechanism by which adiponectin exerts its role in improving insulin sensitivity. Both adiponectin and TNF-α are hormones secreted by adipocytes, which have great similarity in spatial structure but have opposite effects on biological characteristics. Among them, TNF-α inhibits insulin-induced tyrosine phosphorylation of insulin receptor and its substrate and down-regulates insulin-sensitive glucose transporter 4 (GLUT4) in adipocytes, thereby participating in the occurrence and development of obesity and insulin resistance; Adiponectin can significantly inhibit the expression of TNF-α mRNA and TNF-α in macrophages, inhibit TNF-α-induced cell adhesion in human aortic endothelial cells, and reverse insulin resistance in mice. Adiponectin can significantly increase the rapid oxidation of free fatty acids in muscle tissue without affecting lipoprotein lipase and insulin levels, lowering serum triglyceride and fatty acid levels, which may be associated with increased beta-oxidation bypass and related to the expression of related enzymes during oxidative phosphorylation. Fruebis et al. extracted a small fragment containing the carboxy-terminal spherical domain of Acrp30 from mouse plasma, called gAcrp30. It was found to have a similar biological activity to Acrp30, increasing the oxidation of free fatty acids in muscle, lowering blood lipid levels and reducing body weight. At the same time, a small amount of a small fragment containing the C-terminal spherical functional region of adiponectin was detected in human plasma. Is this fragment hydrolyzed by adiponectin, and does it have a similar biological activity to adiponectin? Studies have shown that adiponectin levels are significantly reduced in patients with coronary heart disease, and low adiponectinemia can be used as a risk factor for predicting macrovascular complications in T2DM. Ouchi et al found that adiponectin can effectively inhibit the conversion of macrophages to foam cells. Physiological concentrations of adiponectin can reduce the content of cholesteryl ester in macrophages, and fat droplets in adiponectin-treated macrophages are significantly reduced; Adiponectin can inhibit A-type macrophage clearance at mRNA or protein levels. At the same time, adiponectin can inhibit the expression of adhesion molecules in vascular endothelial cells and inhibit the production of cytokines in macrophages, which provides a more comprehensive basis for its effective anti-atherosclerosis; macrophages pass the secretion of inflammatory cytokines, antigen expression and its phagocytic ability and play an extremely important role in the body's immune system. Studies have found that adiponectin has a significant inhibitory effect on macrophages, which inhibits the phagocytic activity of mature macrophages, thereby controlling early inflammatory responses. The median fluorescence intensity assay shows that adiponectin treatment can be reduced by nearly 2/3 activity of macrophages; at the same time, it significantly inhibits lipopolysaccharide (LPS)-induced TNF-α production and TNF-α mRNA expression in macrophages but has no effect on IL-1β and IL-6 mRNA expression. In addition, adiponectin inhibits the growth of macrophage precursors and the conversion of monocytes to macrophages without direct killing effect on the latter. Adiponectin plays a much positive role in preventing excessive and prolonged inflammatory reactions, both in the early or late stages of inflammation. Many cytokines such as IL-4 and IL-10 inhibit the synthesis of TNF-α in macrophages, but unlike adiponectin, they also have the same inhibitory effects on IL-1β and IL-6. Transforming growth factor beta also inhibits cytokine production in macrophages during the initial stages of the inflammatory response, but its inhibition of TNF occurs in the post-transcriptional phase. Therefore, adiponectin can be used as a unique anti-inflammatory factor that is different from the above cytokines and specifically acts on the transcriptional stage of TNF-α. Prostaglandin E (PGE) also inhibits the synthesis of TNF-α without affecting IL-1α and IL-2β, but studies have found that indomethacin, a PGE synthesis inhibitor, has no effect on TNF-α inhibition by adiponectin. Adiponectin does not function through the PGE bypass. The complement factor C1q shares high homology with adiponectin in the amino acid sequence, and C1qRp is one of the receptors for C1q in phagocytic cells. Studies have found that monoclonal antibodies to MoAb R3 and C1qRp completely block the inhibitory effect of adiponectin on macrophage phagocytosis without influencing the inhibitory effect of adiponectin on TNF-α transcription, suggesting that C1qRp is an adiponectin. One of the receptors that play a biological role at least mediates its inhibition of macrophage phagocytosis. Studies have shown that adiponectin can specifically inhibit the growth of primary granulocyte cell lines in a dose-dependent manner, but has no effect on erythroid and lymphoid lines, and this effect is independent of helper cells. At the same time, adiponectin can induce apoptosis of acute granulocyte leukemia cell lines and acute monocytic leukemia cell lines. Adiponectin can regulate the expression of apoptosis-related genes in mouse granulocyte cell line (M1 cells), down-regulate the expression of anti-apoptotic genes, especially bcl-2, but has no effect on pro-apoptotic genes such as bax, bak, and p53. The specific inhibition of the primary granulocyte cell line by adiponectin is not blocked by MoAb R3, suggesting that this effect is not through the C1qRp bypass.
  2. Pathway regulatin
    Adiponectin is mainly produced and expressed by white adipose tissue, and it has been reported that brown adipose tissue is also involved in the expression of adiponectin. Studies have shown that insulin sensitizer thiazolidinediones (TZDs) can stimulate adiponectin secretion, increase serum adiponectin concentration and large molecular weight adiponectin multimer ratio, even in insulin-sensitive patients using TZDs Plasma adiponectin can still be increased by 130% after 2 weeks of treatment. Some hormones that induce insulin resistance can down-regulate the expression of adiponectin. For example, β-adrenergic agonists can inhibit adiponectin mRNA levels in human and mouse adipocytes in vitro; Glucocorticoids can lower 3T3-L1 cells secretion of adiponectin and the level of mRNA. Nishizawa and other studies have found that plasma adiponectin levels are lower in men than in women  because androgen inhibits the expression of adiponectin in adipocytes. Physical exercise can regulate the expression of adiponectin receptor mRNA in tissues, which can increase muscle sugar uptake and fatty acid oxidation. Physical exercise under certain conditions can also increase the level of serum adiponectin. In addition, in women who are severely obese, effective weight loss increases plasma adiponectin levels and thus improves liver insulin sensitivity.
  3. Relationship with diseases
    Liver damage
    The study found that the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the blood of rats treated with adiponectin increased significantly, hepatocyte necrosis and apoptosis were observed, and the study showed a high mortality rate. If the testing rats were pretreated with adiponectin, the serum AST and ALT levels would increase, the number of hepatocyte necrosis and apoptosis decreased, and the mortality decreased. At
    the same time, serum and liver TNF-α levels and liver PPAR-γ were also  reduced.
    Atherosclerosis
    An animal model of atherosclerosis confirmed that a negative correlation between plasma adiponectin content, triglyceride and low-density lipoprotein was positively correlated with high-density lipoprotein. The cytoprotective effect of adiponectin on atherosclerotic lesions, in addition to its regulation of lipid metabolism, also affects the secretory function of vascular endothelial cells. Adiponectin inhibits the conversion of macrophages to foam cells, and thus adiponectin may act as a regulator of regulation of foam cell formation. It provides a basis for the intrinsic link between vascular inflammation and atherosclerosis.
    Diabetes
    The study found that insulin sensitivity increased, and hyperglycemia was alleviated after a physiological dose of spherical adiponectin was injected into a mouse model of obesity and atrophy. In skeletal muscle, adiponectin increased the expression of certain molecules in fatty acid metabolism, such as fatty acid transporters, and uncoupling protein 2; in the liver, it reduces CD36 expression. It is indicated that adiponectin lowers the concentration of free fatty acids in skeletal muscle and liver circulating blood by promoting the uptake and metabolism of fatty acids by skeletal muscle to relieve insulin resistance of hyperinsulinemia.

References

  1. Liu Y, Sweeney G. Adiponectin action in skeletal muscle. Best Practice & Research Clinical Endocrinology & Metabolism. 2014, 28(1):33-41.
  2. Declercq V, D'Eon B, Mcleod R S. Fatty acids increase adiponectin secretion through both classical and exosome pathways. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2015, 1851(9):1123-1133.
  3. Hebbard L, Ranscht B. Multifaceted roles of adiponectin in cancer. Best Pract Res Clin Endocrinol Metab. 2014, 28(1):59-69.
  4. Dong Z, Su L, Esmaili S, et al. Adiponectin attenuates liver fibrosis by inducing nitric oxide production of hepatic stellate cells. Journal of Molecular Medicine. 2015, 93(12):1327-1339.
  5. Sood A, Seagrave J C, Herbert G, et al. High sputum total adiponectin is associated with low odds for asthma. Journal of Asthma Research. 2014, 51(5):459-466.

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