Adipose tissue is considered an endocrine organ, secreting a number of bioactive molecules called adipokines. Due to the development of obesity and consequent macrophage infiltration, adipose tissue increases the secretion of these bioactive mediators, including adiponectin, resistin, leptin, and plasminogen activator inhibitor-1 (PAI-1), that are involved in many biological processes, such as metabolism, inflammation, and vascular diseases. Adiponectin, the major adipocyte-secreted protein, links visceral adiposity with insulin resistance and atherosclerosis. Unlike other adipokines, adiponectin circulating concentrations are inversely proportional to adiposity. During the past 20 years, several studies established that adiponectin has important roles in metabolic and inflammatory/anti-inflammatory processes (Caselli et al. 2014).
Biosynthesis and Secretion
Adiponectin is mainly secreted by adipocytes, although it can also be produced by cardiomyocytes, hepatocytes, and placenta at lower concentrations. Adiponectin is largely secreted from white adipose tissue and specifically by mature adipocytes. Three major adipose tissue deposits are recognized as producers of this protein: subcutaneous, visceral, and perivascular.
Adiponectin is present in peripheral circulation in very high concentration (2–30 μg/mL). The secretion of adiponectin is controlled by two molecular endoplasmic reticulum chaperones: endoplasmic reticulum protein 44 (44 kDa ER) and endoplasmic reticulum oxidoreductin 1-like alpha (Ero1-Lα) proteins, both induced during adipogenesis. ERp44 forms a disulfide bond with adiponectin, which is important for the maturation of trimeric and hexameric proteins of LMW, MMW, and HMW in oligomers. It is also involved in the specific intracellular retention of adiponectin, so that the overexpression of ERp44 reduces the secretion of the adipokine. The Ero1-Lα protein, in turn, is a close partner of ERp44 and is involved in the weakening of the disulfide covalent bond between adiponectin and ERp44 and consequently the release of adiponectin (Turer and Scherer 2012).
The role of adiponectin is largely mediated by two receptors known as adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2). These receptors have seven transmembrane domains, but are functionally different from the G protein–coupled receptors. Although ubiquitously expressed, the presence of these two receptors may vary from tissue to tissue: AdipoR1 is most abundant in skeletal muscle, while AdipoR2 expression is mostly restricted in the liver (Yamauchi et al. 2003). Both receptors can elicit a series of downstream signaling events. Overexpression of AdipoR1 activates AMP-activated protein kinase, (AMPK) in the liver, suppresses hepatic gluconeogenesis and de novo lipogenesis, and promotes fatty acid oxidation (Yamauchi et al. 2007). AdipoR1 ablation impairs adiponectin-mediated activation of AMPK and silent information regulator 1 (SIRT1), producing an insulin resistant state (Iwabu et al. 2010). On the other hand, the function of AdipoR2 has been debated and still requires further investigation. An additional cell surface molecule called T-cadherin shows significant affinity for adiponectin. T-cadherin binds to adiponectin, but this is not a signaling receptor due to lack of intracellular signaling domains, to confer full cardioprotective potential to the latter (Ruan and Dong 2016).
Adiponectin elicits several downstream signaling events. However, both AdipoR1 and AdipoR2 have no intrinsic protein kinase activity or phosphorylation in response to adiponectin. Thus, they are likely transmembrane receptors that undergo conformational change and link the intracellular domain with other signaling molecules upon extracellular adiponectin binding. The molecules adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 and 2 (APPL1 and APPL2) were identified as intracellular binding partners of adiponectin receptors in various tissues and cell types. APPL1 and APPL2 exert opposite actions in mediating adiponectin signaling (Wang et al. 2009). APPL1 directly binds to the intracellular domains of AdipoR1 and AdipoR2 via its C-terminal domains, thereby mediating the actions of adiponectin in the regulation of energy metabolism and insulin sensitivity. APPL2 negatively modulates adiponectin signaling in skeletal muscle cells.
Adiponectin Signaling and Insulin Sensitivity
Adiponectin signaling in insulin sensitivity involves mainly the AMPK and the peroxisome proliferator-activated receptor (PPAR) pathways. AMPK, a protein kinase regulated by AMP, is a widely recognized cellular sensor for metabolic state. In skeletal muscle, both full-length adiponectin and the globular domain have been shown to trigger, through APPL1, AMPK phosphorylation, leading to AMPK activation (Wu et al. 2003). In skeletal muscle cells isolated from obese individuals, AMPK phosphorylation in response to adiponectin is greatly reduced, suggesting that signaling downstream of the adiponectin receptor may affect the actions of adiponectin, causing adiponectin resistance (Chen et al. 2005). Adiponectin has also been shown to induce AMPK phosphorylation in the liver (Yamauchi et al. 2002).
On the other hand, another key transcription factor in metabolic regulation is PPAR-α. In skeletal muscle, adiponectin drastically increases the expression and activity of PPAR-α, which in turn upregulates acetyl CoA oxidase (ACO), thus inducing fatty acid oxidation and energy expenditure (Yamauchi et al. 2003). In the liver, adiponectin upregulates several PPAR-α target genes, which modulate hepatic fatty acid uptake and metabolism (Yamauchi et al. 2001), and ACO, which regulates fatty acid oxidation (Yamauchi et al. 2001). Moreover, adiponectin has been shown to increase hepatic glucose uptake via PPAR-α, thus improving hepatic insulin sensitivity (Yamauchi and Kadowaki 2013). Thiazolidinedione (TZD) class of PPAR-γ ligands upregulates adiponectin expression in adipocytes. The effect of TZDs on modulating glucose tolerance is impaired in adiponectin-deficient mice, suggesting that adiponectin mediates, at least in part, the insulin-sensitizing actions of TZDs. The expression of PPAR-γ is markedly increased in 3T3-L1 cells overexpressing adiponectin, which is associated with enhanced adipocyte differentiation, suggesting that adiponectin promotes the PPAR-γ pathway, thereby activating a positive feedback loop that induces an increase of adiponectin expression and adipocyte differentiation (Fu et al. 2005).
In addition to these pathways, other multiple pathways mediate the pleiotropic effects of adiponectin. Adiponectin has been shown to induce calcium release from sarcoplasmic reticulum in myocytes or promote calcium influx, thereby activating Ca2+/calmodulin-dependent protein kinase kinase (CaMKK-b) and AMPK, which determinate in activation of SIRT1 and PPAR-α and increase of mitochondria biogenesis (Iwabu et al. 2010). Moreover, ceramide-mediated pathways also have been involved in adiponectin signaling by regulating the actions of both AdipoR1 and AdipoR2. These receptors are associated with ceramidase activities, which, upon adiponectin binding, potently enhances ceramides conversion to Sphingosine-1-phosphate (S1P), independently of AMPK (Holland et al. 2011). Finally, the p38 MAPK pathway also plays a role in adiponectin signaling (Xin et al. 2011).
Adiponectin, Inflammation, and Cardiovascular Disease
Beside vascular compartment, adiponectin exerts protective action also in cardiac compartment, acting and being involved in several molecular pathways of cardiovascular derangement. During heart failure, the levels of adiponectin increase in peripheral circulation due to higher adipose tissue production, stimulated by increased plasma level of natriuretic peptides. Paradoxically, higher adiponectin plasma levels do not induce “adiponectin resistance” at the myocardial level, as indicated by the upregulation of AdipoRs. Locally produced adiponectin in cardiac tissue is not dependent on its circulating levels. Decreased expression of cardiac adiponectin did not have any effect on AMPK activity and TNFα, iNOS, and PPARα expression, suggesting the lack of involvement of metabolism, apoptosis, inflammation, nitrative stress, and remodeling in this model of rodent heart failure (Caselli et al. 2014).
Although adiponectin can be considered as an anti-inflammatory adipokine with cardioprotective role, some studies have indicated that its level is related more closely to the degree of insulin resistance than to the degree of adiposity in humans and that the relationship between adiponectin concentration and cardiovascular disease (CVD) is still controversial. Possible explanations could be responsible for discrepant observations: the different forms of adiponectin found in plasma and their diverse biological effects; and that adiponectin acts differently depending on the receptor activated. Some authors defend that adiponectin can be used as a marker of cardiovascular risk, once it correlates negatively with coronary artery disease, although depending on which receptor is activated make it still a controversial issue (Ouchi et al. 1999). Nevertheless, it is generally well accepted that hypoadiponectinemia (<4 μg/mL) is associated with a variety of diseases, including atherosclerosis, diabetes, hypertension, and others, although hyperadiponectinemia can be associated with increased renal and pulmonary diseases as well as a worst heart failure prognosis (Kishida et al. 2014).
While adiponectin itself is not a suitable candidate for drugs, the components of the adiponectin signaling pathway are promising therapeutic targets. Some aspects of adiponectin action could be taken into account with the potential for drug development: (1) tissue-specific functions of adiponectin; (2) adiponectin receptors AdipoR1, AdipoR2, and T-cadherin; (3) signaling through adiponectin receptor; (4) crosstalks of adiponectin signaling pathway with other pathways involved in metabolic regulation; and (5) pathways independent from adipoR (Caselli et al. 2014). Thus, small molecules that enhance adiponectin signaling may be viable options for the treatment of obesity-linked metabolic diseases including type 2 diabetes. Recent studies show that a small-molecule activator of the adiponectin receptor, AdipoRon, improves glucose tolerance and ameliorates insulin resistance in mice fed a high-fat diet (Okada-Iwabu et al. 2013). Furthermore, AdipoRon improves metabolic parameters and prolongs life span in db/db mice, a genetic mouse model for diabetes (Okada-Iwabu et al. 2013). However, more studies are needed in order to better identify the affinity and the potential use of small molecules such as AdipoRon.
In conclusion, several issues have to be clarified related to adiponectin, including how the adiponectin signaling pathway is regulated and the phenomenon of adiponectin resistance. Thorough understanding of adiponectin and its downstream signaling pathways will provide a guide for the development of novel drugs in the treatment of obesity-related metabolic diseases.
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