Endocrine Abstracts

Toll-like receptor 4 (TLR4) has a critical role in innate immunity, and the activation of inflammatory pathways plays an important role in the induction of insulin resistance. Indeed, we have recently demonstrated that TLR4 is implicated in resistin-induced inflammation and insulin resistance in the hypothalamus.¹ We have also shown that TLR4 is up-regulated in the hypothalamus of mice fed a high-fat diet. Here, we aim to decipher the molecular mechanisms implicated in the regulation of TLR4 expression. For this purpose, human neuroblastoma cells (SHSY-5Y) were exposed during 4 h to either palmitic acid (a saturated fatty acid) or the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA). Cells were then treated with resistin. Firstly we analysed the effect of resistin, palmitic acid and DHA on inflammation markers. We show that only resistin was able to activate NF-κB and to increase the phosphorylation of Akt and p38 MAPK. However, palmitic acid pretreatment increases the expression of inflammatory cytokines (IL-6 and TNF-α), similar to resistin. Interestingly, DHA pretreatment suppresses palmitic acid and resistin induced up-regulation of IL-6 and TNF-α. Secondly, we studied the possible synergistic interaction between resistin and palmitic acid on TLR-4 expression. We show that palmitic acid pretreatment increases TLR4 expression, at both protein and mRNA levels, while DHA pretreatment had no effect. Importantly, palmitic acid pretreatment potentiates resistin effects. In conclusion, we show for the first time, to our knowledge, that palmitic acid induces TLR4 expression and this leads to the amplification of resistin effects promoting then insulin resistance at the neuronal level.

Reference: 1. Benomar et al., Diabetes. 2013 62 102–14.

Disclosure: This work was supported by funds from University of Paris Sud and the CNRS (Centre National de la Recherche Scientifique, France).