Endocrine Abstracts

Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. Resistin is secreted by adipose tissue and macrophages, but its mechanism of action remained unknown because its receptor was not characterised. Recently, we have shown that central resistin acts by way of hypothalamic TLR4 receptors promoting overall inflammation and insulin resistance. Here, we aim to block resistin action in HFD mice that are prone to obesity and inflammation, and attempt to reverse these metabolic disorders. For this purpose, we have developed recombinant human resistin mutant (C6A) that does not form the dimeric molecule of resistin and acts as resistin antagonist (RA). The quality and purity of RA has been verified by SDS–PAGE and SEC analysis. Firstly, we tested the efficacy of RA in human neuronal cells SH-SY5Y and in mouse hypothalamic cell line. We showed that resistin (100 ng/ml) induced the phosphorylation of Akt, while RA had no such activity in both cell lines. Importantly, RA (10 mg/ml) treatment totally abolished resistin-dependent Akt phosphorylation. Once, the efficacy of RA demonstrated, we attempted to reverse the HFD-dependent insulin resistance by RA treatment in vivo. For this purpose, we have fed male C57BL/6 mice with HFD for 6 weeks and then mice received for 14 days daily injection of RA (0.3 mg/day per mice). We clearly show that RA leads to a significant decrease in body weight of HFD mice mainly due to loss of visceral fat. Importantly, RA treatment significantly improved both glucose tolerance and insulin responsiveness of HFD mice. Interestingly, hypothalamic IL6 expression, and reactive gliosis in the arcuate nucleus were markedly reduced in RA-treated HFD mice. Collectively, these findings indicates that the blockade of resistin action reduced body weight gain, visceral fat content and hypothalamic inflammation and restored insulin responsiveness of mice fed high fat diet.

Disclosure: This work was supported by funds from Univeristy Paris Sud and CNRS (centre national de la Recherche Scientifique), France.