Oxidative and endoplasmic reticulum (ER) stress are involved in mediating high-fat diet (HFD)-induced insulin resistance. As the ER-localized methionine sulfoxide reductase B3 (MsrB3) protects cells against oxidative and ER stress, we hypothesized that MsrB3 might be associated with HFD-induced insulin resistance. To test this hypothesis, we examined the effect of MsrB3 deficiency on HFD-induced insulin resistance using MsrB3 knockout (KO) mice. Mice were fed a control diet or HFD for 12 weeks and insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. HFD consumption increased the body weight of both wild-type and MsrB3 KO mice, and no significant difference was observed between the genotypes. The HFD increased oxidative stress and induced insulin resistance in the skeletal muscle of wild-type mice, but did not affect either in MsrB3 KO mice. The unfolded protein response (UPR) was increased in MsrB3 KO mice upon consumption of HFD, but not in wild-type mice. Mitochondrial oxidative phosphorylation proteins and the levels of superoxide dismutase 2 and glutathione peroxidase 1 were increased in MsrB3 KO mice upon HFD consumption. The respiratory control ratio was reduced in wild-type mice consuming HFD but not in MsrB3 KO mice. The levels of calcium/calmodulin-dependent protein kinase kinase β, phosphorylated AMP-activated protein kinase, and peroxisome proliferator-activated receptor gamma coactivator 1α were increased in MsrB3 KO mice following HFD consumption. These results suggest that MsrB3 deficiency inhibits HFD-induced insulin resistance, and the increased mitochondrial biogenesis and antioxidant induction might be the mechanisms underlying this phenomenon.

氧化和内质网（ER）应激参与介导高脂饮食（HFD）诱导的胰岛素抵抗。由于ER定位的蛋氨酸亚砜还原酶B3（MsrB3）保护细胞免受氧化和ER应激，我们假设MsrB3可能与HFD诱导的胰岛素抵抗有关。为了验证该假设，我们使用MsrB3敲除（KO）小鼠检查了MsrB3缺乏对HFD诱导的胰岛素抵抗的影响。给小鼠喂食对照饮食或HFD，持续12周，并使用高胰岛素-正常血糖钳测量胰岛素敏感性。食用HFD会增加野生型和MsrB3 KO小鼠的体重，并且在基因型之间未观察到显着差异。HFD增加了野生型小鼠骨骼肌的氧化应激并诱导了胰岛素抵抗，但对MsrB3 KO小鼠均无影响。食用HFD后，MsrB3 KO小鼠的未折叠蛋白应答（UPR）增加，而野生型小鼠则没有。食用HFD后MsrB3 KO小鼠线粒体氧化磷酸化蛋白和超氧化物歧化酶2和谷胱甘肽过氧化物酶1的水平增加。食用HFD的野生型小鼠的呼吸控制率降低，而MsrB3 KO小鼠的呼吸控制率却没有降低。食用HFD后MsrB3 KO小鼠的钙/钙调蛋白依赖性蛋白激酶激酶β，磷酸化的AMP激活的蛋白激酶和过氧化物酶体增殖物激活的受体γ共激活子1α的水平增加。这些结果表明，MsrB3缺乏会抑制HFD诱导的胰岛素抵抗，