title: Integrin-Linked Kinase in Muscle Is Necessary for the Development of Insulin Resistance in Diet-Induced Obese Mice.
abstract: Diet-induced muscle insulin resistance is associated with expansion of extracellular matrix (ECM) components, such as collagens, and the expression of collagen-binding integrin, α2β1. Integrins transduce signals from ECM via their cytoplasmic domains, which bind to intracellular integrin-binding proteins. The integrin-linked kinase (ILK)-PINCH-parvin (IPP) complex interacts with the cytoplasmic domain of β-integrin subunits and is critical for integrin signaling. In this study we defined the role of ILK, a key component of the IPP complex, in diet-induced muscle insulin resistance. Wild-type (ILK(lox/lox)) and muscle-specific ILK-deficient (ILK(lox/lox)HSAcre) mice were fed chow or a high-fat (HF) diet for 16 weeks. Body weight was not different between ILK(lox/lox) and ILK(lox/lox)HSAcre mice. However, HF-fed ILK(lox/lox)HSAcre mice had improved muscle insulin sensitivity relative to HF-fed ILK(lox/lox) mice, as shown by increased rates of glucose infusion, glucose disappearance, and muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. Improved muscle insulin action in the HF-fed ILK(lox/lox)HSAcre mice was associated with increased insulin-stimulated phosphorylation of Akt and increased muscle capillarization. These results suggest that ILK expression in muscle is a critical component of diet-induced insulin resistance, which possibly acts by impairing insulin signaling and insulin perfusion through capillaries.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, U.K. l.kang@dundee.ac.uk.
authors.forename: Li
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Mokshagundam
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Bradley
authors.initials: B
authors.lastname: Reuter
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Lark
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, U.K.
authors.forename: Claire C
authors.initials: CC
authors.lastname: Sneddon
authors.affiliation: Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, U.K.
authors.forename: Chandani
authors.initials: C
authors.lastname: Hennayake
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: Deanna P
authors.initials: DP
authors.lastname: Bracy
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN Department of Medicine, Veterans Affairs Hospital, Nashville, TN.
authors.forename: Ambra
authors.initials: A
authors.lastname: Pozzi
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University, Nashville, TN Department of Medicine, Veterans Affairs Hospital, Nashville, TN.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN.
authors.forename: David H
authors.initials: DH
authors.lastname: Wasserman
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005109:Extracellular Matrix / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D000099200:Scaffold Protein ILK
chemical_list: D005947:Glucose; D007328:Insulin; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK