title: Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice.
abstract: We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Indumathi
authors.initials: I
authors.lastname: Chennamsetty
authors.affiliation: Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Coronado
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kévin
authors.initials: K
authors.lastname: Contrepois
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Keller
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Carcamo-Orive
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sandin
authors.affiliation: Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.affiliation: Department of Psychiatry, Stanford University, Stanford, CA 94305, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Whittle
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Fathzadeh
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Gerald
authors.initials: G
authors.lastname: Reaven
authors.affiliation: Department of Biochemistry, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Attie
authors.affiliation: Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Division of Cardiovascular Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: knowlej@stanford.edu.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
mesh_terms: D041721:3T3-L1 Cells; D000255:Adenosine Triphosphate / Q000096:biosynthesis; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism; D010805:Physical Conditioning, Animal; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1
keywords: NAT2; Nat1; adipose tissue; basal metabolic rate; fatty acids; insulin resistance; mitochondria; mitochondrial dysfunction; reactive oxygen species