title: Central resistin overexposure induces insulin resistance through Toll-like receptor 4.
abstract: 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 NH(2)-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.
authors.affiliation: Unité Mixte de Recherche 8195, University Paris-Sud, Orsay, France.
authors.forename: Yacir
authors.initials: Y
authors.lastname: Benomar
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.forename: Pamela
authors.initials: P
authors.lastname: De Lacy
authors.forename: Delphine
authors.initials: D
authors.lastname: Crépin
authors.forename: Hassina
authors.initials: H
authors.lastname: Ould Hamouda
authors.forename: Laure
authors.initials: L
authors.lastname: Riffault
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
mesh_terms: D000818:Animals; D001921:Brain / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D052243:Resistin / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D052243:Resistin; D051197:Toll-Like Receptor 4; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases