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  • Autocrine regulations of several adipokines e g leptin and r

    2023-03-17

    Autocrine regulations of several adipokines (e.g., leptin and resistin) on adipocytes have been reported (Karastergiou and Mohamed-Ali, 2010, Ye et al., 2010). Several lines of evidence have shown that apelin influences adipocyte functions, such as, lipolysis and glucose uptake (Dray et al., 2008, Yue et al., 2011). And apelin receptors are known to be expressed in adipocytes (Wei et al., 2005, Castan-Laurell et al., 2008). These suggest the autocrine regulations of apelin on adipocytes through apelin receptors. It has been shown that anti-lipolysis effect of apelin on adipocytes is absent in apelin receptor null mice (Yue et al., 2011). Here, we demonstrate that apelin receptor expression and apelin secretion share common AT1 and AT2 signaling pathways, implying the intimate collaboration between apelin and apelin receptor. In support of this notion, we also discovered that either application of apelin or activation of AT1 receptor prevents β-adrenergic agonist induced lipid droplet fragmentation (data not shown). Adipose tissue is highly vascularized allowing significant crosstalks between apelin-secreting adipocytes and AngII-secreting vascular endothelial UCM05 (Schling and Loffler, 2002). It has been reported that apelin promotes angiogenesis in adipose tissue (Kunduzova et al., 2008), which in turn may facilitate adipose tissue growth (Schling and Loffler, 2002). Increased vascularization may lead to higher local AngII level. And activation of AT1 by high level of AngII would stimulate apelin secretion. In addition, it has been shown that AngII can stimulate human visceral adipocyte growth via AT1 receptor (Sarzani et al., 2008). Increased adiposity shall then lead to higher local apelin level. Taken together, a positive feedback loop involving apelin and AngII/AT1 receptor seems to exist to facilitate adipose tissue growth. This notion may provide mechanistic insights to the common association between obesity and hypertension. The counteracting AT2 signaling shall provide a route to balance or rectify the positive loop constituted by apelin and AT1 signaling. Interestingly, it has been reported that AT1-receptor-blocking anti-hypertension drugs (e.g., valsartan, telmisartan) can reduced adipocyte size, adipose tissue mass and body weight gain in animal models (Mori et al., 2007, Munoz et al., 2009, He et al., 2010) and human (Kakuma, 2009). These may be attributable to the de-shadowing of AT2 influences in the absence of AT1 activation. It is conceivable that AT2 receptor could be a novel therapeutic target to treat obesity and obesity induced hypertension. In conclusion, this study reveals a new regulatory mechanism on apelin secretion from adipocytes. Based on the present findings, it may be pictured that, determined by the intriguing balance between the counteracting AT1 and AT2 signaling, AngII modulates adipocyte functions (e.g., lipolysis and glucose uptake) via autocrine regulation by apelin-APJ system and influences metabolic functions of other cells at paracrine and endocrine levels through released apelin.
    Acknowledgment This study was supported by a NMRC grant (EDG11may011) from the National Medical Research Council (Singapore).
    Introduction The liver is primarily responsible for energy metabolism, and its function is greatly affected by pathological conditions, such as, hepatic steatosis. Nonalcoholic hepatic steatosis, a condition of extensive lipid accumulation in hepatocytes, is strongly associated with metabolic syndrome, which includes obesity, insulin resistance, and type II diabetes [1]. De novo lipogenesis contributes significantly to hepatic steatosis [2], [3], and liver X receptor α (LXRα; a nuclear receptor) serves as a crucial sterol sensor, and plays a critical role in the regulation of hepatic fatty acid synthesis by activating sterol regulatory element binding protein 1c (SREBP-1c), a key transcription factor for the regulation of hepatic lipogenesis [4]. Furthermore, the hepatic expressions of LXRα and SREBP-1c are elevated in steatosis patients [5]. In addition, an animal experiment showed treatment with LXRα agonist enhanced hepatic triglyceride levels and increased SREBP-1c expression [6].