Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice. / Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper; Chukijrungroat, Natsasi; Petersen, Kitt Falk; Shulman, Gerald I.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 52, 12.2017, p. E11285-E11292.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice
AU - Camporez, João Paulo
AU - Wang, Yongliang
AU - Faarkrog, Kasper
AU - Chukijrungroat, Natsasi
AU - Petersen, Kitt Falk
AU - Shulman, Gerald I.
PY - 2017/12
Y1 - 2017/12
N2 - 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.
AB - 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.
KW - Ceramides
KW - Diacylglycerol
KW - Mitochondria
KW - Protein kinase ϵ
KW - Protein kinase θ
U2 - 10.1073/pnas.1716990115
DO - 10.1073/pnas.1716990115
M3 - Journal article
C2 - 29237750
AN - SCOPUS:85039703472
VL - 114
SP - E11285-E11292
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 52
ER -
ID: 188228181