Endocrine Abstracts

Obesity is linked to common metabolic diseases including insulin resistance, which constitutes a principal risk factor for type 2 diabetes. Increasing evidence indicates that changes in adipose-secreted factors in obesity, dramatically affect insulin sensitivity. Among these adipokines, resistin is described as a key factor in obesity-mediated both inflammation and insulin resistance. However, little is known about the molecular mechanisms mediating resistin effects particularly at the neuronal level. Recently, we have shown that central resistin acts by way of hypothalamic TLR4 receptors promoting overall inflammation and insulin resistance. Adiponectin is another adipokine with anti-diabetic and insulin sensitizing properties. A decrease in adiponectin level and action has been linked to insulin resistance. Here, we aim to investigate whether resistin could contribute to insulin resistance trough the impairment of adiponectin action. To test this hypothesis we examined the impact of resistin overexposure on adiponectin signaling in human neuronal cells SH-SY5Y. Interestingly, we show that resistin treatment completely abolished adiponectin-dependent Akt phosphorylation whereas ERK1/2 was not affected. Importantly, resistin treated SH-SY5Y cells showed a marked down-regulation of adiponectin receptor (AdipoR1) and APPL1, a critical mediator of both adiponectin and insulin signaling. This has been confirmed in vivo. Indeed, in Wistar rats, chronic ICV resistin infusion (14 days) markedly reduced hypothalamic expression of APPL1 AdipoR1 and AdipoR2. Furthermore, to assess whether resistin action on adiponectin signalling is mediated by TLR4, we generated TLR4-depleted SH-SY5Y cells. Interestingly, the knock-down of TLR4 completely abrogates the resistin-dependent down regulation of AdipoR1 and APPL1 and totally restablished adiponectin-dependent phosphorylation of AKT. Collectively, these results indicate that resistin-dependent activation of TLR4 promotes the down regulation of APPL-1 and adiponectin receptors leading to the alteration of adiponectin signalling. This could contribute, at least in part, to the impairment of the insulin-sensitizing effect of adiponectin at the neuronal level.

Disclosure: This work was supported by funds from university Paris Sud and CNRS (Centre National de la recherche Scientifique), France.