title: MsrA Overexpression Targeted to the Mitochondria, but Not Cytosol, Preserves Insulin Sensitivity in Diet-Induced Obese Mice.
abstract: There is growing evidence that oxidative stress plays an integral role in the processes by which obesity causes type 2 diabetes. We previously identified that mice lacking the protein oxidation repair enzyme methionine sulfoxide reductase A (MsrA) are particularly prone to obesity-induced insulin resistance suggesting an unrecognized role for this protein in metabolic regulation. The goals of this study were to test whether increasing the expression of MsrA in mice can protect against obesity-induced metabolic dysfunction and to elucidate the potential underlying mechanisms. Mice with increased levels of MsrA in the mitochondria (TgMito MsrA) or in the cytosol (TgCyto MsrA) were fed a high fat/high sugar diet and parameters of glucose homeostasis were monitored. Mitochondrial content, markers of mitochondrial proteostasis and mitochondrial energy utilization were assessed. TgMito MsrA, but not TgCyto MsrA, mice remain insulin sensitive after high fat feeding, though these mice are not protected from obesity. This metabolically healthy obese phenotype of TgMito MsrA mice is not associated with changes in mitochondrial number or biogenesis or with a reduction of proteostatic stress in the mitochondria. However, our data suggest that increased mitochondrial MsrA can alter metabolic homeostasis under diet-induced obesity by activating AMPK signaling, thereby defining a potential mechanism by which this genetic alteration can prevent insulin resistance without affecting obesity. Our data suggest that identification of targets that maintain and regulate the integrity of the mitochondrial proteome, particular against oxidative damage, may play essential roles in the protection against metabolic disease.
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, Texas, United States of America.
authors.forename: JennaLynn
authors.initials: J
authors.lastname: Hunnicut
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, Texas, United States of America.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center and Oklahoma City VA Medical Center, Oklahoma, Oklahoma, United States of America.
authors.forename: Arlan
authors.initials: A
authors.lastname: Richardson
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, Texas, United States of America; Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas, United States of America.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Salmon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000378:metabolism*; D059305:Diet, High-Fat; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051150:Methionine Sulfoxide Reductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D055372:AMP-Activated Protein Kinases