title: Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance.
abstract: In the current study, we used muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis.
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL garveyt@uab.edu siweizh@uab.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Mengrui
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Medicine-Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Teayoun
authors.initials: T
authors.lastname: Kim
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ravi H
authors.initials: RH
authors.lastname: Jariwala
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: W John
authors.initials: WJ
authors.lastname: Garvey
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Nanlan
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Minsung
authors.initials: M
authors.lastname: Kang
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ma
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ling
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Dennis
authors.initials: D
authors.lastname: Steverson
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Yuchang
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL Birmingham Veterans Affairs Medical Center, Birmingham, AL garveyt@uab.edu siweizh@uab.edu.
authors.forename: W Timothy
authors.initials: WT
authors.lastname: Garvey
mesh_terms: D000818:Animals; D001823:Body Composition / Q000235:genetics / Q000502:physiology; D002153:Calorimetry, Indirect; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D007328:Insulin; D012097:Repressor Proteins; C474830:TRB3 protein, mouse; C474831:TRIB3 protein, human; D002784:Cholesterol; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose