Article open access publication

Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice

Proceedings of the National Academy of Sciences of the United States of America, Proceedings of the National Academy of Sciences, ISSN 0027-8424

Volume 114, 52, 2017

DOI:10.1073/pnas.1716990115, Dimensions: pub.1099663131, PMC: PMC5748223, PMID: 29237750,

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  1. (1) Yale University, grid.47100.32
  2. (2) University of Copenhagen, grid.5254.6, KU

Description

A single-nucleotide polymorphism in the human arylamine N-acetyltransferase 2 (Nat2) gene has recently been identified as associated with insulin resistance in humans. To understand the cellular and molecular mechanisms by which alterations in Nat2 activity might cause insulin resistance, we examined murine ortholog Nat1 knockout (KO) mice. Nat1 KO mice manifested whole-body insulin resistance, which could be attributed to reduced muscle, liver, and adipose tissue insulin sensitivity. Hepatic and muscle insulin resistance were associated with marked increases in both liver and muscle triglyceride (TAG) and diacylglycerol (DAG) content, which was associated with increased PKCε activation in liver and increased PKCθ activation in skeletal muscle. Nat1 KO mice also displayed reduced whole-body energy expenditure and reduced mitochondrial oxygen consumption in white adipose tissue, brown adipose tissue, and hepatocytes. Taken together, these studies demonstrate that Nat1 deletion promotes reduced mitochondrial activity and is associated with ectopic lipid-induced insulin resistance. These results provide a potential genetic link among mitochondrial dysfunction with increased ectopic lipid deposition, insulin resistance, and type 2 diabetes.

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University of Copenhagen

Danish Open Access Indicator

2017: Realized

Research area: Medicine

Danish Bibliometrics Indicator

2017: Level 2

Research area: Medicine

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Times Cited: 16

Field Citation Ratio (FCR): 10

Relative Citation ratio (RCR): 0.99

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