Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction

Jennalynn Styskal, Florence A. Nwagwu, Yvonne N. Watkins, Hanyu Liang, Arlan Richardson, Nicolas Musi, Adam Salmon

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA-/-) are prone to the development of high-fat-diet-induced insulin resistance and a reduced physiological insulin response compared to high-fat-fed wild-type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high-fat-fed mice show similar reduction in insulin receptor function and increase in insulin receptor oxidation, which are further exacerbated by the lack of MsrA. Together, these data demonstrate for the first time that MsrA and protein oxidation play a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.

Original languageEnglish (US)
Pages (from-to)123-132
Number of pages10
JournalFree Radical Biology and Medicine
Volume56
DOIs
StatePublished - Mar 2013

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Methionine Sulfoxide Reductases
Insulin Resistance
Insulin
Insulin Receptor
Oxidation
Obesity
Oxidative stress
Fats
Proteins
Oxidative Stress
High Fat Diet
Methionine
Phosphorylation
Homeostasis
Nutrition
Cell Culture Techniques
Polymorphism
Cell culture
Genome
Glucose

Keywords

  • Diabetes
  • Glucose homeostasis
  • Methionine sulfoxide
  • Obesity
  • Oxidative stress
  • Protein oxidation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction. / Styskal, Jennalynn; Nwagwu, Florence A.; Watkins, Yvonne N.; Liang, Hanyu; Richardson, Arlan; Musi, Nicolas; Salmon, Adam.

In: Free Radical Biology and Medicine, Vol. 56, 03.2013, p. 123-132.

Research output: Contribution to journalArticle

Styskal, Jennalynn ; Nwagwu, Florence A. ; Watkins, Yvonne N. ; Liang, Hanyu ; Richardson, Arlan ; Musi, Nicolas ; Salmon, Adam. / Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptorfunction. In: Free Radical Biology and Medicine. 2013 ; Vol. 56. pp. 123-132.
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