title: Toll-like receptors 2 and 4 impair insulin-mediated brain activity by interleukin-6 and osteopontin and alter sleep architecture.
abstract: Impaired insulin action in the brain represents an early step in the progression toward type 2 diabetes, and elevated levels of saturated free fatty acids are known to impair insulin action in prediabetic subjects. One potential mediator that links fatty acids to inflammation and insulin resistance is the Toll-like receptor (TLR) family. Therefore, C3H/HeJ/TLR2-KO (TLR2/4-deficient) mice were fed a high-fat diet (HFD), and insulin action in the brain as well as cortical and locomotor activity was analyzed by using telemetric implants. TLR2/4-deficient mice were protected from HFD-induced glucose intolerance and insulin resistance in the brain and displayed an improvement in cortical and locomotor activity that was not observed in C3H/HeJ mice. Sleep recordings revealed a 42% increase in rapid eye movement sleep in the deficient mice during daytime, and these mice spent 41% more time awake during the night period. Treatment of control mice with a neutralizing IL-6 antibody improved insulin action in the brain as well as cortical activity and diminished osteopontin protein to levels of the TLR2/4-deficient mice. Together, our data suggest that the lack of functional TLR2/4 protects mice from a fat-mediated impairment in insulin action, brain activity, locomotion, and sleep architecture by an IL-6/osteopontin-dependent mechanism.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tuebingen, Otfried-Mueller-Straße 10, D-72076 Tuebingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Sartorius
authors.forename: Stefan Z
authors.initials: SZ
authors.lastname: Lutz
authors.forename: Miriam
authors.initials: M
authors.lastname: Hoene
authors.forename: Jens
authors.initials: J
authors.lastname: Waak
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.forename: Cora
authors.initials: C
authors.lastname: Weigert
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.forename: Anita M
authors.initials: AM
authors.lastname: Hennige
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000502:physiology*; D002478:Cells, Cultured; D004569:Electroencephalography; D005951:Glucose Tolerance Test; D007328:Insulin / Q000502:physiology*; D007333:Insulin Resistance; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D008124:Locomotion; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D053495:Osteopontin / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012890:Sleep; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
chemical_list: D007328:Insulin; D015850:Interleukin-6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt