JennaLynn HunnicutYuhong LiuArlan RichardsonAdam B. Salmon2017-03-052017-03-052015-10-08Hunnicut J, Liu Y, Richardson A, Salmon AB (2015) MsrA Overexpression Targeted to the Mitochondria, but Not Cytosol, Preserves Insulin Sensitivity in Diet-Induced Obese Mice. PLoS ONE 10(10): e0139844. doi:10.1371/journal.pone.0139844http://hdl.handle.net/11244/49279The authors thank Dr. Rod Levine and his laboratory at NIH/NHLBI for sharing MsrA transgenic and knockout mice.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.en-USAttribution 3.0 United StatesMitochondria,Obesity,Insulin,Oxidation,Methionine,Insulin resistance,Fats,DietResearch Article10.1371/journal.pone.0139844false