title: Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding.
abstract: Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6-8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding.
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia; Metabolic Phenotyping Core, Virginia Tech, Blacksburg, Virginia; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, Virginia;
authors.forename: Ryan P
authors.initials: RP
authors.lastname: McMillan
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Yaru
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Kevin
authors.initials: K
authors.lastname: Voelker
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fundaro
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: John
authors.initials: J
authors.lastname: Kavanaugh
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, Virginia;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Stevens
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan; and.
authors.forename: Elika
authors.initials: E
authors.lastname: Shabrokh
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Mostafa
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Mordecai
authors.initials: M
authors.lastname: Harvey
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia;
authors.forename: Angela S
authors.initials: AS
authors.lastname: Anderson
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, Virginia;
authors.forename: Nabil E
authors.initials: NE
authors.lastname: Boutagy
authors.affiliation: Gene Nutrient Interactions, Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Mynatt
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia; Metabolic Phenotyping Core, Virginia Tech, Blacksburg, Virginia; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, Virginia;
authors.forename: Madlyn I
authors.initials: MI
authors.lastname: Frisard
authors.affiliation: Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, Virginia; Metabolic Phenotyping Core, Virginia Tech, Blacksburg, Virginia; Fralin Translational Obesity Research Center, Virginia Tech, Blacksburg, Virginia; hulvermw@vt.edu.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Hulver
mesh_terms: D000222:Adaptation, Physiological; D000821:Animal Feed; D000818:Animals; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Toll-like receptor 4; fatty acid oxidation; high-fat diet; reactive oxygen species; skeletal muscle