Biochemistry, Adiponectin

Fundamentals

Adiponectin was originally thought to be secreted only from the adipose tissue and acts on the skeletal muscle cells in an endocrine manner. However, more recent studies have shown that adiponectin is also produced by the skeletal muscle cells, functioning in an autocrine/paracrine fashion through interacting with adiponectin receptor (AdipoR) 1 and AdipoR2. In addition, endothelial cells have also been reported to express adiponectin. However, the prevailing consensus is that adiponectin is predominantly produced by adipocytes. Adiponectin directly acts on the liver, skeletal muscle, and vasculature through insulin sensitization and anti-inflammatory/anti-atherogenic effects.[1][6]

Cellular Level

Adiponectin is synthesized and secreted mainly by the white adipocytes. Adiponectin is composed of an N-terminal sequence, a hypervariable domain, 15 collagenous repeats, and a C-terminal domain. The HMW form of adiponectin is the most bioactive form of adiponectin in plasma. Generally, women have higher concentrations of both total and HMW adiponectin than males.[7]

Molecular Level

Adiponectin is a 244 amino acid protein predominantly secreted by white adipose tissue. The protein is encoded by the Adipo Q gene on chromosome locus 3q27. The adiponectin protein contains an NH2-terminal hyper-variable region, a collagenous domain of 22 Gly-XY repeats, and a COOH-terminal C1q-like globular domain. Secretion of adiponectin into the bloodstream is as three oligomeric complexes. These complexes include a trimer, a hexamer, and a high molecular weight multimer.

Biosynthesis and consequent secretion of adiponectin are modulated by chaperone proteins such as endoplasmic reticulum resident protein 44, ER oxidoreductase 1-LA, and disulfide-bond A oxidoreductase-like protein. Extensive post-translational modification occurs through actions such as endoplasmic reticulum resident protein 44 retaining adiponectin oligomers in the endoplasmic reticulum and ER oxidoreductase 1-LA releasing these same adiponectin oligomer complexes. Other important actions include sialic acids dictating the half-life of adiponectin through glycosylation of threonine residues within the hypervariable region and succination of cysteine residues in hypervariable regions of adiponectin to block adiponectin multimerization.

Adiponectin predominantly binds to seven transmembrane receptors called AdipoR1 and AdipoR2. In contrast to classic G-protein coupled receptors, these two receptors have a cytoplasmic NH2 terminus and extracellular COOH terminal domain. AdipoR1 is expressed most abundantly in skeletal muscle, while adipoR2 is expressed predominantly in the liver. AdipoR1 mediates cross-communication between insulin and adiponectin and interacts directly with insulin receptor substrates. Adiponectin relatively has a short half-life of 45 to 75 minutes despite its minimal degradation during circulation. Adiponectin is cleared predominantly by the liver but can also bind pancreatic beta cells and certain heart and kidney cell types.[1]

Function

Adiponectin holds a variety of critical metabolic and cellular functions that ultimately determine its role in the pathobiology of human diseases.

Adiponectin performs many metabolic functions that link to energy metabolism. For instance, adiponectin mediates insulin sensitivity in skeletal muscle through AMP kinase and peroxisome proliferator-activated receptor alpha (PPAR-alpha). In the liver, adiponectin upregulates glucose transport and down-regulates gluconeogenesis through AMP-activated protein kinase (AMPK) while activating fatty acid oxidation and decreasing inflammation via PPAR-alpha. Adiponectin increases insulin sensitivity in the liver as well through upregulating phosphorylation of the insulin receptor and insulin substrate receptor 1. Additionally, it also increases insulin secretion from the pancreas. Adiponectin also enhances basal glucose and insulin-stimulated glucose uptake by activating AMPK in adipose tissues.[1][2]

Adiponectin has been shown to play a significant role in the modulation of inflammation. More specifically, studies have exhibited that adiponectin decreases inflammation in macrophages, endothelial tissue, muscle, and epithelial cells through cyclic AMP-protein kinase A and AMPK activation. There is evidence that adiponectin prevents the production of reactive oxidative species and promotes down-regulation of inflammation. Moreover, adiponectin has been shown to inhibit CRP secretion and suppress pathways involving NF-kB signaling and TNF-α. These functions elucidate adiponectin as exhibiting potential protective functions in inflammatory diseases such as atherosclerosis.[2][8]

Recently, adiponectin has been shown to regulate cell proliferation, which has been shown to counter cell growth and induce apoptosis. For instance, one study highlighted adiponectin's role in counteracting carcinogenesis through AMPK stimulation and consequent activation of p21 and p23 in colon cancer cells. The tumor-suppressing effects of adiponectin have also shown promise in lung and pancreatic cell lines. However, several recent studies have also demonstrated adiponectin's anti-apoptotic and proliferative roles.[9]

Mechanism

Adiponectin receptors (AdipoR1 and AdipoR2) mediate the signaling of adiponectin. AdipoR1 is highly expressed in skeletal muscle, whereas AdipoR2 is mainly expressed in the liver. While AdipoR1 has a higher affinity for the globular form of adiponectin than for full-length adiponectin. AdipoR2 has an intermediate affinity for both globular and full-length adiponectin.

Upon binding to AdipoR1, adiponectin increases glucose uptake and fatty acid oxidation in skeletal muscle, which is mediated by recruitment of the adaptor protein containing pleckstrin homology domain, phosphotyrosine domain, and leucine zipper domain (APPL). APPL binding to the intracellular region of AdipoR1 activates Rab5, a small GTPase that increases the membrane translocation of glucose transporter-4 (GLUT4) and glucose uptake in muscle. APPL also binds to PI3 kinase and Akt, indicating that adiponectin also can enhance insulin signaling.[10][11]

The interaction of APPL and AdipoR1 stimulates the activation of AMP-activated protein kinase (AMPK), which inhibits acetyl-CoA carboxylase (ACC), which increases fatty acid oxidation—adipoR-mediated activation of AMPK results in increased fatty acid oxidation and decrease adiposity. AMPK activation also leads to an increase in glucose uptake and lactate production in muscle and suppresses gluconeogenesis. Together, the signaling mechanisms of adiponectin highlight the importance of adiponectin in glucose and lipid metabolism.[12]

Clinical Significance

As a widely studied biomarker, adiponectin has been shown to play a role in various endocrine and metabolic disorders. Continued research regarding the role it plays as a biomarker has the potential to elucidate further the pathogenesis and treatment of disease. Associations between adiponectin and these various types of dysfunction are listed below.

Body Weight Studies demonstrate that obese patients have decreased levels of mRNA and serum levels of adiponectin. Conversely, these levels are increased in extremely lean patients suffering from conditions such as anorexia nervosa. Various cross-sectional studies have established an inverse relationship between adiponectin serum levels and BMI. Notably, an even stronger inverse relationship exists between adiponectin serum levels and fat mass. Weight loss through means such as diet and exercise and bariatric surgery has resulted in increased plasma levels of adiponectin in patients.[13]

Insulin Resistance

Studies involving rodent models have demonstrated the role of adiponectin in promoting insulin sensitization. Moreover, numerous positive correlations between insulin resistance and hypoadiponectinemia have been established in humans. Hypoadiponectinemia is a feature in pathologies such as gestational diabetes, type 2 diabetes, and diabetes associated with lipodystrophy. Further, low adiponectin levels have been demonstrated in patients with insulin resistance regardless of obesity.

Strong genetic associations between adiponectin levels and insulin resistance have also been established. For instance, a genetic polymorphism on chromosome 3 resulting in hypoadiponectinemia increases susceptibility to the development of insulin resistance and metabolic syndrome. Adiponectin has become such a powerful clinical biomarker that low levels of it predict the future onset of insulin resistance. This may explain why thiazolidinediones and PPARS-gamma agonists are the most potent insulin sensitizer drugs in our diabetic armamentarium, and adiponectin upregulation potentially mediates this effect. This benefit also extends to patients with non-alcoholic steatohepatitis.[13][14]

Lipodystrophy

Adiponectin has also been shown to have significant associations with lipodystrophy. This is particularly important as metabolic derangements like insulin resistance, diabetes, and dyslipidemia often accompany lipodystrophy. Congenital and HIV-related lipodystrophies are also associated with low levels of adiponectin. Additionally, patients undergoing treatment with highly active antiretroviral therapy (HAART) have developed lipodystrophies. Studies demonstrate that HAART therapy lowers adiponectin in these patients, which suggests another inverse relationship between lipodystrophy and adiponectin levels.[13]

Atherosclerosis

Various adipokines have been shown to mediate communication between adipose tissues, the heart, and different vasculatures. Moreover, there is an altered release of these adipokines in cardiovascular diseases and atherosclerosis. Adiponectin is a beneficial player in patients with atherosclerosis. For instance, low adiponectin levels predict a higher incidence of adverse cardiovascular events such as myocardial infarctions and atherosclerosis.

Serum adiponectin levels have also been shown to have an inverse relationship with intimal thickness, an important biomarker of atherosclerosis. At the cellular level, adiponectin has also demonstrated a role in slowing the transformation of macrophages to foam cells and consequently stalling progression to atherosclerosis in animal models. However, serum adiponectin does not yet enjoy acceptance as a risk marker for ASCVD prediction or management.[13]

Metabolic Syndrome

Adiponectin is shown to play an important role in metabolic syndrome, a pathology characterized by continuous low-grade inflammation. For example, adiponectin levels demonstrate an inverse correlation with adiposity and proinflammatory cytokines in patients suffering from metabolic syndrome. Also, low levels of 'high molecular weight' adiponectin levels are associated with the future development of the metabolic syndrome.[9]

The above associations represent only several examples of the vast pool of pathologies that show links to adiponectin. Other pathologies include diabetic retinopathy and various cancers. Because adiponectin has such strong links to the pathogenesis of inflammatory disease, it could be a valuable biomarker and treatment target.

Consequently, treatments have emerged that increase serum levels of adiponectin. Non-pharmaceutical treatments include sustained physical exercise and caloric restriction. Supplements include curcumin, capsaicin, and gingerol. Long-standing pharmaceutical therapies such as metformin and thiazolidinediones have demonstrated increased secretion of adiponectin and improved outcomes in patients suffering from chronic diseases such as type 2 diabetes. Recombinant adiponectin and adiponectin agonists could be potential treatments for chronic inflammatory diseases.[9]