title: Central Resistin/TLR4 Impairs Adiponectin Signaling, Contributing to Insulin and FGF21 Resistance.
abstract: Adiponectin, an insulin-sensitizing hormone, and resistin, known to promote insulin resistance, constitute a potential link between obesity and type 2 diabetes. In addition, fibroblast growth factor (FGF)21 has effects similar to those of adiponectin in regulating glucose and lipid metabolism and insulin sensitivity. However, the interplay between adiponectin, FGF21, and resistin signaling pathways during the onset of insulin resistance is unknown. Here, we investigated whether central resistin promotes insulin resistance through the impairment of adiponectin and FGF21 signaling. We show that chronic intracerebroventricular resistin infusion downregulated both hypothalamic and hepatic APPL1, a key protein in adiponectin signaling, associated with decreased Akt-APPL1 interaction and an increased Akt association with its endogenous inhibitor tribbles homolog 3. Resistin treatment also decreased plasma adiponectin levels and reduced both hypothalamic and peripheral expression of adiponectin receptors. Additionally, we report that intracerebroventricular resistin increased plasma FGF21 levels and downregulated its receptor components in the hypothalamus and peripheral tissues, promoting FGF21 resistance. Interestingly, we also show that resistin effects were abolished in TLR4 knockout mice and in neuronal cells expressing TLR4 siRNAs. Our study reveals a novel mechanism of insulin resistance onset orchestrated by a central resistin-TLR4 pathway that impairs adiponectin signaling and promotes FGF21 resistance.
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
authors.forename: Yacir
authors.initials: Y
authors.lastname: Benomar
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
authors.forename: Hamza
authors.initials: H
authors.lastname: Amine
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
authors.forename: Délphine
authors.initials: D
authors.lastname: Crépin
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Al Rifai
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Riffault
authors.affiliation: Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Arieh
authors.initials: A
authors.lastname: Gertler
authors.affiliation: UMR 9197, Molecular Neuroendocrinology of Food Intake, University Paris-Sud, Orsay, France Department of Molecules and Circuits, CNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France mohammed.taouis@u-psud.fr.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Taouis
mesh_terms: D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004351:Drug Resistance / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D057967:Infusions, Intraventricular; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D052243:Resistin / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D052242:Adiponectin; D052243:Resistin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors