title: Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo.
abstract: Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCε, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Galbo
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: João-Paulo G
authors.initials: JP
authors.lastname: Camporez
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Alves
authors.forename: Mario
authors.initials: M
authors.lastname: Kahn
authors.forename: Blas A
authors.initials: BA
authors.lastname: Guigni
authors.forename: Julie
authors.initials: J
authors.lastname: Serr
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhang
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D004075:Diglycerides / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D004042:Dietary Fats, Unsaturated; D004075:Diglycerides; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; C526299:Irs2 protein, rat; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4