Figure 6

This figure summarizes the central s-resistin downregulation effects on hypothalamic and peripheral insulin and leptin sensitivity. Knocked down central s-resistin by ICV injection of lentiviral RNAi, improves hypothalamic insulin pathway increasing IRβ and IRS-1 activity by the up-regulation in tyrosine phosphorylation. In agreement with that, the inhibitory Ser307-phosphorylation of IRS-1 decreased in treated rats together with the JNK activity, major responsible of IRS-1 Ser-phosphorylation. The improvement of central insulin signalling is also supported by the fall of PTP-1B expression and protein activation, possibly due to the improvement of the inflammatory state (see below). Besides, the hypothalamus raises its leptin sensibility by increasing STAT-3 activation that promotes POMC expression and prevent the NPY one. The downregulation of TNFα, IL-6, iNOS, JNK and the transcription factor NK-κB combined with the upregulation of IL-10 support a decrease on the inflammatory status in the hypothalamus of treated rats. All these improvements in the central inflammatory state contribute equally to ameliorate the hypothalamic insulin and leptin signalling. Also, the reduction of central s-resistin decreased adipokines secretion and enhanced peripheral insulin sensitivity. Take together all these results indicate that s-resistin could be a key player implicated in the development of central insulin resistance and inflammatory disease.