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APJ expression in metabolic diseases
Under physiological conditions, APJ is present in humans as well as in mouse tissues with high metabolic activity such as muscle and adipose tissue but not in the liver. Moreover, the presence and regulation of APJ in established adipocyte or muscle cell lines is less clear. With obesity, expression of APJ, like apelin, was increased in adipose tissue and this increase was closely related to plasma insulin concentrations (Boucher et al., 2005). However, this regulation by insulin was different according to the severity of insulin resistance. During the fasting/refeeding transition or in the fed state, the gene expression of APJ was significantly increased in adipose tissue of HFD mice but not in db/db mice (an obese mouse model of T2D due to a mutation in the leptin receptor). In muscle, APJ gene expression was not changed during this transition and decreased dramatically in db/db muscle (Dray et al., 2010). Thus the regulation of APJ expression was different in adipose tissue and muscle. This difference was also found in mice that received fat diet supplemented (or not) with a polyunsaturated fatty acid, the eicosapentaenoic acid. Indeed, eicosapentaenoic LDE225 Diphosphate mg associated with HFD protects mice from obesity and prevents the development of metabolic alterations in muscle compared to mice fed only with HFD (Bertrand et al., 2013). These beneficial effects are accompanied by an increased APJ gene expression in muscle but not in adipose tissue (Bertrand et al., 2013).
In humans, APJ gene expression regulation in adipose tissue and muscle were similar to those described in mice. APJ expression increased in adipose tissue of obese women and decreased following weight loss induced by a low calorie diet (Castan-Laurell et al., 2008). In adipose tissue of healthy and type 2 diabetic patients, no significant difference was found in the basal state (Dray et al., 2010). However in biopsies taken before and after an hyperinsulinemic–euglycemic clamp, APJ expression increased only in adipose tissue of the control subjects. In muscle, although there was no difference in APJ expression between control and diabetic subjects, insulin infusion during the clamp caused an increase of APJ mRNA in both groups (Dray et al., 2010). By contrast, in a study in which obese subjects (but not diabetics) performed a physical training program of eight weeks, the expression of APJ remained unchanged in muscle biopsies taken before and after training whereas the expression of apelin was increased (Besse-Patin et al., 2014).
Plasma apelin concentrations and its forms in healthy humans
Since the discovery of apelin, several studies reported the plasma concentrations of apelin in human health and disease. Methods used for apelin quantification include enzyme immunoassays and radioimmunoassays. Nevertheless, using these approaches, the reported circulating levels in healthy persons varies greatly from one study to another oscillating between few picograms per milliliter (pg/ml) to several nanograms per milliliter (ng/ml) (for review: (Charles, 2008)). Moreover, to determine the specific forms of apelin present in the plasma but also in different tissues, gel filtration or high-performance liquid chromatography (HPLC) separation coupled with apelin-like immunoreactivity detection were employed. Using these approaches, contradicting results were reported in the literature regarding the different forms identified in the plasma of healthy subjects. Indeed, in rat plasma, immunoreactive apelin was determined to be [Pyr-1]-apelin-13 and apelin-17 (De Mota et al., 2004) whereas in human plasma, those two forms of apelin were identified with apelin-36 (Azizi et al., 2008). However, an initial report identified apelin fragments, in human plasma, with molecular weight significantly higher than that of apelin-36 (Foldes et al., 2003). Conversely, Miettinen et al. described an immunoreactive apelin with a retention time comparable with apelin-13 (Miettinen et al., 2007).