title: Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptor function.
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.
authors.affiliation: The Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Jennalynn
authors.initials: J
authors.lastname: Styskal
authors.forename: Florence A
authors.initials: FA
authors.lastname: Nwagwu
authors.forename: Yvonne N
authors.initials: YN
authors.lastname: Watkins
authors.forename: Hanyu
authors.initials: H
authors.lastname: Liang
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D011972:Receptor, Insulin / Q000378:metabolism
chemical_list: D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D011972:Receptor, Insulin; D005947:Glucose