Resistin induces insulin resistance through Toll-Like Receptor 4 in SH-SY5Y human neuronal cells

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 818-841-Diabetes Pathophysiology & Complications
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-824
Mohammed Taouis*1, Yacir Benomar2, Arieh Gertler3, Pamela de Lacy4, Delphine Crepin5, Hassina ould Hamouda5 and Laure Riffault5
1University of Paris XI, Chilly Mazarin, France, 2University of Paris-Sud, France, 3Hebrew Univ Inst of Biochemist, Rehovot, Israel, 4Shenandoah Biotechnology, 5University of Paris-Sud
Resistin induces insulin resistance through Toll-Like Receptor 4 in SH-SY5Y human neuronal cells.

Yacir Benomar1,2, Arieh Gertler3, Pamela De Lacy4, Delphine Crépin1,2, Hassina Ould Hamouda1,2, Laure Riffault1,2 and Mohammed Taouis1,2

 1Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, Franc;,2Centre National de la Recherche Scientifique, Center of Neurosciences Paris-Sud, Unité Mixte de Recherche 8195, Orsay, France ; 3Faculty of Agricultural, Food and Environmental Quality Sciences, The Institute of Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel;  4Shenandoah Biotechnology, Inc. Warwick, Pennsylvania.

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, including release of inflammatory cytokines, dramatically affect insulin sensitivity. Among these adipokines, resistin is described as a key factor in obesity-mediated both inflammation and insulin resistance. More recently, it has been shown that resistin acts within the hypothalamus to modulate feeding and energy homeostasis.  However, the resistin receptor has not yet been identified, and little is known about the molecular mechanisms underlying resistin effects, particularly at the neuronal levels. Thus in the present study we aimed to characterize neuronal resistin receptor and its signaling pathways involved in the impairment of insulin responsiveness. Using human neuroblastoma cell line SH-SY5Y we show that resistin overexposure inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and ERK 1/2 associated with reduced IR expression and with upregulation of SOCS-3 and PTP-1B, two negative regulators of insulin signaling. Additionally, we show that resistin treatment promotes the activation of the serine kinases JNK and p38 MAPK, enhances the serine phosphorylation of IRS-1, and increases the expression of the proinflammatory cytokine IL-6. Interestingly, we also demonstrate, using cross-linking experiments, that resistin directly bind to TLR4 receptor in SH-SY5Y cells leading to the recruitment of the adaptor proteins MyD88 and TIRAP. Furthermore, we report that the invalidation of TLR4 expression using siRNA, markedly reduced resistin binding to TLR4 and the resistin-induced activation of JNK and p38MAPK pathways, preventing the onset of insulin resistance in this neuronal cells. In conclusion, our findings identified Toll TLR4 as resistin’s receptor, and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistnace at the neuronal levels.

Nothing to Disclose: MT, YB, AG, PD, DC, HO, LR

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