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  • br Introduction As is now well known obesity is major


    Introduction As is now well known, obesity is major risk factor for various diseases such as nonalcoholic fatty liver disease, cardiovascular disease, some cancers (McWilliams and Petersen, 2009), type-2 diabetes mellitus (Jakobsen et al., 2007), and hypertension (Aneja et al., 2004), among others. Although many studies have revealed related genes and signaling pathways, the underlying mechanism of obesity remains unclear (Larson-Meyer et al., 2006). Resistin, an adipocytokine which was first identified in 2001 (Steppan et al., 2001), has been reported to be involved in many metabolism-associated diseases such as insulin resistance (IR), hyperglycemia, and atherosclerosis (AS) (Kim et al., 2001). When resistin concentration was lowered by a specific antisense oligodeoxynucleotide in high fat diet (HFD) fed mice, insulin action was considerably improved in vivo (Muse et al., 2004). Accumulated evidence showed that hyperglycemia always accompanied high serum concentrations of resistin (Pagano et al., 2006). Endothelial cell layers act as a blood–tissue barrier, regulating transfer of small molecules across the barrier and thus controlling their assimilation by different tissues (Yang et al., 2014). This raised the question of whether the retention of glucose in plasma was caused by the dysfunction of the endothelial cell layer. In general, mammalian blood–tissue barriers consisting of endothelial Metabolism Compound Library regulate the exchange of nutrients between plasma and tissues (Marzesco et al., 2002). The paracellular pathway and transmembrane transport are two methods of material transport. The paracellular pathway strictly limits small molecules and ions to diffuse across the paracellular space (Balda and Matter, 2008). It relies on the function of tight junctions, which are made up of several proteins including claudins, occludins and tight junction protein 1 (TJP1, also known as ZO-1). All of these proteins are enriched in endothelial cells (Rubin, 1992). Besides the paracellular pathway, small molecules can transfer across cell layers by transmembrane transport. This relies on a variety of different transmembrane transporters and glucose transporter proteins (GLUTs) facilitate the transfer of glucose across cell membranes. Early studies showed that resistin could inhibit glucose uptake in rat muscle cells (Fan et al., 2007). This was due to downregulated expression as well as tyrosine phosphorylation of IRS-1 and decreased GLUT4 translocation by resistin (Palanivel et al., 2006). S-resistin, a non-secretable resistin variant had the similar effect with resistin. Both of them could restrain 3T3-L1 pre-adipocyte differentiation and impair glucose uptake in 3T3-L1 cells by decreasing the expression of GLUT4 (Fernandez et al., 2010). GLUT1 (Zhao et al., 2015), a core glucose transporter protein which is enriched in the blood–brain barrier, blood–ocular barrier and placental barrier (Tserentsoodol et al., 1998), facilitates the transendothelial transport of glucose to tissue (Klepper, 2015). Impaired S226 phosphorylation in GLUT1 is a characteristic of some GLUT1 deficiency syndromes and causes reduced glucose transport in endothelial cells (Lee et al., 2015). However, the relationship between resistin and GLUT1 was not very clear. Since previous studies have indicated that hyperglycemia is accompanied by high serum concentrations of resistin (Li et al., 2006), we felt it was necessary to further investigate the association between them. Here, we analyzed the effect of resistin on glucose transportation in EA.hy926 cells and investigated the underlying mechanism through which resistin exerted its effect.
    Discussion Mounting evidence indicates that high plasma glucose concentrations caused by resistin (Gomez-Diaz et al., 2012) are due to the impaired tissue insulin sensitivity which results in diminished glucose absorption (Li et al., 2006). In fact the dysfunction of endothelial barriers might also result in hyperglycemia, since glucose transport would be inhibited, causing the retention of glucose in plasma. However, few studies have focused on the effect of resistin on glucose transport from blood to tissue. In this study, we show that the permeability of glucose is inhibited after resistin treatment (Fig. 1B). The measurement of intracellular glucose concentration further confirmed this finding (Fig. 1C). The glucose accumulation in serum caused by the impaired glucose transport in endothelial cells might offer a new explanation for hyperglycemia.