title: SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat-Fed Mice.
abstract: Protein hyperacetylation is associated with glucose intolerance and insulin resistance, suggesting that the enzymes regulating the acetylome play a role in this pathological process. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has been linked to energy homeostasis. Thus, it is hypothesized that the dysregulation of the mitochondrial acetylation state, via genetic deletion of SIRT3, will amplify the deleterious effects of a high-fat diet (HFD). Hyperinsulinemic-euglycemic clamp experiments show, for the first time, that mice lacking SIRT3 exhibit increased insulin resistance due to defects in skeletal muscle glucose uptake. Permeabilized muscle fibers from HFD-fed SIRT3 knockout (KO) mice showed that tricarboxylic acid cycle substrate-based respiration is decreased while fatty acid-based respiration is increased, reflecting a fuel switch from glucose to fatty acids. Consistent with reduced muscle glucose uptake, hexokinase II (HKII) binding to the mitochondria is decreased in muscle from HFD-fed SIRT3 KO mice, suggesting decreased HKII activity. These results show that the absence of SIRT3 in HFD-fed mice causes profound impairments in insulin-stimulated muscle glucose uptake, creating an increased reliance on fatty acids. Insulin action was not impaired in the lean SIRT3 KO mice. This suggests that SIRT3 protects against dietary insulin resistance by facilitating glucose disposal and mitochondrial function.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN louise.lantier@vanderbilt.edu.
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
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.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Williams
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Karen K
authors.initials: KK
authors.lastname: Yang
authors.affiliation: Department of Molecular Physiology and Biophysics, 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.
authors.forename: Mickael
authors.initials: M
authors.lastname: Goelzer
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN.
authors.forename: Freyja D
authors.initials: FD
authors.lastname: James
authors.affiliation: Departments of Radiation Oncology and Pharmacology and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL.
authors.forename: David
authors.initials: D
authors.lastname: Gius
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: D000107:Acetylation; D000818:Animals; D059305:Diet, High-Fat; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; C525046:Sirt3 protein, mouse; D006593:Hexokinase; D056566:Sirtuin 3