APN accounts for of total plasma proteins in humans this

APN accounts for 0.01% of total plasma proteins in humans; this proportion increases with age to a small extent (Barb et al., 2007). Normal APN levels in the circulation range 3–30μg/mL (Aprahamian and Sam, 2011). APN levels are lower in men than women due to the presence of testosterone and even more so in obese men as opposed to normal-weight men as there is a negative correlation between APN levels and increasing BMI (Dalamaga et al., 2012, Ziemke and Mantzoros, 2010). For instance, according to Hotta et al. (2001), higher serum levels of APN (increase of 65%) were seen to occur with a lower BMI of 12%. The APN plasma concentration increases under certain nutritional states such as a hypercaloric diet, smoking, etc (Pischon et al., 2005). In general, plasma APN concentration is directly proportional to caloric restriction weight loss (Barb et al., 2007). Studies have demonstrated that plasma APN levels are low in relation to obesity and insulin resistance (Chandran et al., 2003). Low APN secretion is due to high TNF-α production in obese patients (Tilg and Moschen, 2006). Cell line, animal and human studies showed that high APN LY2784544 and secretion, principally resulting from the HMW isoform, are commonly treated with PPAR-γ and thiazolidinediones but not the common diabetic drug metformin (Cariou et al., 2012, Davies et al., 2013). Angiogenesis is driven by pro-angiogenic proteins for example, the endothelial cell membrane protein thrombospondin (Muppala et al., 2015). APN is also involved in the regulation of angiogenesis, indicating its role in migration of HUVEC thus inducing blood vessel formation in vivo (Bråkenhielm et al., 2004). Thus the pro-angiogenic role of APN leads to increased anti-diabetic effects (Vaiopoulos et al., 2012). There are contradictory studies arguing for an anti-angiogenic role for APN (Garaulet et al., 2007). APN is involved in the regulation of key mediators of innate immunity and also influences the expression of multiple genes having anti-inflammatory properties in cultured macrophages (Yokota et al., 2000) (Folco et al., 2009). Further, APN is implicated in suppressing B-cell lymphopoiesis (Yokota et al., 2003). In addition, APN induces cell cycle arrest and cell death by suppressing the cAMP/PKA pathway (Li et al., 2011). Especially, APN treatment downregulated the expression of cyclin D and Bcl-2 and upregulated the expression of p53 and Bax, and led to cell cycle arrest and cell death (Dieudonne et al., 2006). APN is involved in the activation of many other signaling pathways such as mTOR, NF-κB, JNK and STAT3 which mediate diseases including metabolic syndrome and cancer (Bråkenhielm et al., 2004). The overall anti-malignant effects of APN are seen in obesity linked cancers (Fujisawa et al., 2008). Low titers of APN have been reported in CRC and PC patients. The pleiotropic features of APN need to be investigated further in order to develop APN-based agents that may combat cancer.
Adiponectin receptors APN has been reported to interact with three receptors, i.e., AdipoR1, AdipoR2 and T-cadherin (Dalamaga et al., 2012). AdipoR1 and AdipoR2 are typically linked to the mediation of fatty acid oxidation and glucose uptake, whereas T-cadherin appears on the cell surface and acts as a receptor and is important for both cell adhesion and communication (Hug et al., 2004). AdipoR1 and AdipoR2 receptors show unique distributions and affinities for the different forms of circulating APN. For example, AdipoR1 shows high affinity for globular protein and low affinity towards the full length APN molecule. In contrast, AdipoR2 shows medium affinity for both of these forms of APN (Goldstein and Scalia, 2004). T-cadherin is known as the third known receptor of APN and is capable of binding to the hexameric and multimeric forms but not to the trimeric and globular forms of APN (Hug et al., 2004). T-cadherin is involved in APN signaling through interactions with APN receptors (Kadowaki and Yamauchi, 2005).