• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • Apelin is involved in various physiological functions includ


    Apelin is involved in various physiological functions, including Edaravone contraction (Ashley et al., 2005), vasodilatation (Jia et al., 2007), feeding control (Valle et al., 2008), and metabolic homeostasis (Higuchi et al., 2007, Dray et al., 2008, Attane et al., 2010). Its plasma level is elevated in obesity (Boucher et al., 2005). As apelin receptors are expressed in adipocytes (Wei et al., 2005, Castan-Laurell et al., 2008), it is not surprising that apelin exerts multifaceted influence on adipose tissue. It increases glucose uptake in adipocytes by enhancing insulin sensitivity (Dray et al., 2008, Yue et al., 2010); regulates secretion of other adipokines (Higuchi et al., 2007); inhibits adipocyte lipolysis (Yue et al., 2011); and promotes angiogenesis in adipose tissue (Kunduzova et al., 2008, Rayalam et al., 2008) and therefore likely adipose tissue growth (Rupnick et al., 2002). Angiotensin II (AngII) is a peptide hormone, well-known for its regulations on blood vessel contraction and angiogenesis (Lucius et al., 1999). In adipose tissue, both white adipocytes and vascular endothelial cells produce AngII (Schling and Loffler, 2002, Engeli et al., 2003, Hung et al., 2010). The plasma level of AngII increases significantly in obesity (Goossens et al., 2003). In adipocytes, AngII has anti-lipolytic as well as lipogenesis effects (Jones et al., 1997, Goossens et al., 2007) and potentiates insulin-stimulated glucose uptake (Juan et al., 2005). It acts through angiotensin type 1 receptor (AT1) and type 2 receptor (AT2) (Dinh et al., 2001). Both receptors are expressed in adipocytes (Mallow et al., 2000, Schling, 2002, Juan et al., 2005). Activation of the two types of receptor triggers distinct signaling pathways and usually produces antagonizing effects (Dinh et al., 2001, Johren et al., 2004). For examples, AT1 signaling stimulates angiogenesis and adipogenesis while AT2 signaling inhibits them (Chung et al., 1996, Di Filippo et al., 2005, Matsushita et al., 2006, Sarzani et al., 2008). Evidences have been demonstrated that AngII modulates secretion of several adipokines, including leptin, interleukin 6 (IL-6), IL-8, and plasminogen activator inhibitor-1 (PAI-1) (Skurk et al., 2001, Skurk et al., 2004, Kim et al., 2002). A recent study showed that inhibition of AngII synthesis or AngII receptors during adipogenesis of 3T3-L1 cells increases apelin expression and secretion (Hung et al., 2010), suggesting the regulatory roles of AngII on apelin secretion. In the present study, we investigated the effects of AngII on apelin secretion and apelin receptor expression in 3T3-L1 adipocytes and elucidated the distinct signaling pathways mediated by AT1 and AT2 receptors, respectively.
    Materials and methods
    Discussion Adipocytes play a central role in energy metabolism through the secretion of adipokines which are in turn regulated by other metabolic factors, such as, insulin (Boucher et al., 2005) and catecholamines (Than et al., 2011a). Here, we demonstrate that apelin secretion in 3T3-L1 adipocytes is differentially regulated by angiotensin type 1 and type 2 receptors. Our results can be fitted into the signaling map illustrated in Fig. 7. AT1 receptor is known to couple with G-protein cascade which, in turn, activates phospholipase C-β (PLC-β) (Griendling et al., 1996, Dinh et al., 2001). PLC-β cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), and DAG together with IP3-induced intracellular release of Ca2+ subsequently activates protein kinase C (PKC). In adipocytes and other cells, PKC can stimulate MAPK kinase which phosphorylates ERK 1/2 (Ranganathan et al., 2002, Fricke et al., 2004). Activation of ERK 1/2 finally leads to increase of apelin expression and secretion. Such scenario of signal transduction is supported by our observations when AT1 receptors were selectively activated by blocking AT2 receptors. Specifically, (1) AngII induced a rise of intracellular Ca2+ in the absence of external Ca2+ (Fig. 4C); (2) depletion of internal Ca2+, but not external Ca2+, suppressed the basal and AngII stimulated apelin secretion (Fig. 4B); (3) activating PKC using the DAG analogue (PMA) increased basal apelin secretion while inhibition of PKC largely abolished AngII induced apelin secretion (Fig. 4A); (4) AngII stimulated phosphorylation of ERK 1/2 (Fig. 5C); (5) inhibition of MAPK kinase abolished AngII enhanced apelin secretion and expression (Fig. 5A and B). Considering the fact that in all secretory cells PKC can potently and acutely stimulate secretion from readily releasable pools (Morgan et al., 2005, Xue et al., 2009, Than et al., 2011b), it is likely that the observed acute effect of AT1 activation on apelin secretion is through MAPK/ERK independent PKC activities. In parallel to the PLC-β pathway as described above, AT1 activation may also stimulate MAPK kinase through PLC-γ (Schieffer et al., 1996). But this alternative path (if exists in 3T3-L1 adipocytes) appears to be insignificant, because inhibition of PKC totally abolished AngII induced apelin secretion. The importance of PKC and MAPK kinase on apelin secretion was also demonstrated by a previous study, which showed that inhibition of PKC and MAPK kinase blocked the insulin-induced apelin expression in mouse adipocytes whereas PMA enhanced it (Boucher et al., 2005).