Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4
- 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, France
- 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
- Corresponding author: Mohammed Taouis, .
Resistin promotes both inflammation and insulin resistance associated with energy homeostasis impairment. However, the resistin receptor and the molecular mechanisms mediating its effects in the hypothalamus, crucial for energy homeostasis control, and key insulin-sensitive tissues are still unknown. In the current study, we report that chronic resistin infusion in the lateral cerebral ventricle of normal rats markedly affects both hypothalamic and peripheral insulin responsiveness. Central resistin treatment inhibited insulin-dependent phosphorylation of insulin receptor (IR), AKT, and extracellular signal–related kinase 1/2 associated with reduced IR expression and with upregulation of suppressor of cytokine signaling-3 and phosphotyrosine phosphatase 1B, two negative regulators of insulin signaling. Additionally, central resistin promotes the activation of the serine kinases Jun NH2-terminal kinase and p38 mitogen-activated protein kinase, enhances the serine phosphorylation of insulin receptor substrate-1, and increases the expression of the proinflammatory cytokine interleukin-6 in the hypothalamus and key peripheral insulin-sensitive tissues. Interestingly, we also report for the first time, to our knowledge, the direct binding of resistin to Toll-like receptor (TLR) 4 receptors in the hypothalamus, leading to the activation of the associated proinflammatory pathways. Taken together, our findings clearly identify TLR4 as the binding site for resistin in the hypothalamus and bring new insight into the molecular mechanisms involved in resistin-induced inflammation and insulin resistance in the whole animal.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0237/-/DC1.
- Received February 28, 2012.
- Accepted July 6, 2012.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.