title: Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance.
abstract: Chronic low-grade inflammation is a hallmark of obesity and thought to contribute to the development of obesity-related insulin resistance. Toll-like receptor 4 (Tlr4) is a key mediator of pro-inflammatory responses. Mice lacking Tlr4s are protected from diet-induced insulin resistance and inflammation; however, which Tlr4-expressing cells mediate this effect is unknown. Here we show that mice deficient in hepatocyte Tlr4 (Tlr4LKO) exhibit improved glucose tolerance, enhanced insulin sensitivity and ameliorated hepatic steatosis despite the development of obesity after a high-fat diet (HFD) challenge. Furthermore, Tlr4LKO mice have reduced macrophage content in white adipose tissue, as well as decreased tissue and circulating inflammatory markers. In contrast, the loss of Tlr4 activity in myeloid cells has little effect on insulin sensitivity. Collectively, these data indicate that the activation of Tlr4 on hepatocytes contributes to obesity-associated inflammation and insulin resistance, and suggest that targeting hepatocyte Tlr4 might be a useful therapeutic strategy for the treatment of type 2 diabetes.
authors.affiliation: 1] Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [2].
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.affiliation: 1] Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [2].
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Vianna
authors.affiliation: 1] Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [2].
authors.forename: Makoto
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: 1] Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [2] Advanced Imaging Research Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Berglund
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Tao
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Tiemin
authors.initials: T
authors.lastname: Liu
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Harper
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.affiliation: Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Syann
authors.initials: S
authors.lastname: Lee
authors.affiliation: Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: 1] Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA [2] Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
mesh_terms: D052436:Adipose Tissue, White / Q000166:cytology / Q000276:immunology; D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D059305:Diet, High-Fat; D004789:Enzyme Activation; D005234:Fatty Liver / Q000235:genetics; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000201:enzymology*; D007249:Inflammation / Q000276:immunology*; D007333:Insulin Resistance / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4