Inhibition by resistin: implication for the regulation of glucose homeostasis

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Resistin is a 12,5-kDa cysteine-rich protein secreted by adipose tissue of rodents and macrophages of humans (Steppan et al., 2001). The hypothesis that resistin could be a possible link between obesity and insulin resistance is controversial in humans in the light of recent studies (Lee et al., 2003; Nagaev and Smith, 2001). In contrast, consistent findings in rodents suggest that resistin plays a causative role in the development of diet-induced insulin resistance. Additionally, some studies support a link between deleterious metabolic effects of resistin and reduction of AMPK activity. Indeed, a significant correlation has been shown between plasma resistin levels with high fat feeding (or acute infusion of recombinant resistin), hepatic insulin resistance and diminished AMPK phosphorylation in liver (Muse et al., 2004). Conversely, treatment with resistin specific antisense oligodeoxynucleotide reversed these effects. In addition, mice lacking resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production (Banerjee et al., 2004). This is partly mediated by activation of AMPK and decreased expression of gluconeogenic enzymes in the liver. Taken together, these data indicated that resistin is a key promoter of hepatic insulin resistance and that this effect could be partly mediated through reduction of hepatic AMPK activity.

Additional studies suggested that resistin acting on hypothalamus modulates hepatic glucose production. Thus, infusion of resistin in the third cerebral ventricle (icv) or in the mediobasal hypothalamus was sufficient to enhance endogenous glucose production through an increase of TNFa, IL-6, and SOCS-3 expression and a decrease of AMPK phosphorylation in the liver (Muse et al., 2007). This suggested that hypothalamus is an important site of resistin action.

It has been also shown that resistin reduces not only insulin-mediated glucose transport in vivo (Satoh et al., 2004) and in isolated muscle cells (Junkin et al., 2009; Niederwanger et al., 2007; Palanivel et al., 2006; Palanivel and Sweeney, 2005); but also AICAR-stimulated glucose uptake in muscle (Jorgensen et al., 2009). Basically, these studies showed that resistin regulates the function of IRS-1 and Akt1 and decreases GLUT4 translocation and glucose uptake in response to insulin. Short-term resistin incubation impairs glycogen synthesis by reducing the rate of glucose-6-phosphate formation by reduction of hexokinase type I activity and reduction of glucose uptake (Niederwanger et al., 2007). Lastly, resistin decreases phosphorylation of muscular AMPK and ACC (Palanivel and Sweeney, 2005). Nevertheless, it can be noted that some studies used supra-physiological concentrations of resistin. This could explain that in a recent study on mouse extensor digitorum longus (EDL), soleus muscles and L6 myotubes, physiological concentrations of resistin impair insulin-stimulated glucose uptake by mechanisms involving reduced plasma membrane GLUT4 translocation but independently of the proximal insulin-signaling cascade, AMPK, and SOCS-3 (Jorgensen et al., 2009).