Session: MON 818-841-Diabetes Pathophysiology & Complications
Poster Board MON-824
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
*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm
See more of: Abstracts - Orals, Featured Poster Presentations, and Posters