Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice

• DOI: 10.1016/j.celrep.2016.09.005
• Publication Date: 2016-10-04T16:47:53Z
• Authors: Indumathi Chennam...; Michael Coronado; Kévin Contrepois; Mark P. Keller; Ivan Carcamo-Orive; John Sandin; Giovanni Fajardo; Andrew J. Whittle; Mohsen Fathzadeh; Michael Snyder; Gerald Reaven; Alan D. Attie; Daniel Bernstein; Thomas Quertermous; Joshua W. Knowles
• Keywords: Exercise intolerance

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 led dysfunction characterized by increased intracellular reactive oxygen species fragmentation well decreased membrane potential, biogenesis, mass, respiration, ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, tissues from Nat1-deficient mice, including white adipose tissue, heart, skeletal muscle. mice had changes plasma metabolites lipids a ability utilize fats for energy decrease basal metabolic rate exercise capacity without altered thermogenesis. Collectively, our results suggest deficiency dysfunction, which may constitute mechanistic link between this gene IR.