Methionine sulfoxide reductase B3 deficiency inhibits the development of diet-induced insulin resistance in mice

Abstract

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.

LXR agonist modifies neuronal lipid homeostasis and decreases PGD2 in the dorsal root ganglia in western diet-fed mice

“…Consistent with previous report 5 , WD feeding upregulated transcripts including Glutathione Peroxidase 7 (GPX7) and Methionine Sulfoxide Reductase B3 (MSRB3) that are involved in mitigating persistent ER stress and associated Unfolded Protein Response (Fig. 2 A) 25 , 26 . We also identified upregulated transcripts involved in triglyceride sequestering, including Oxysterol Binding Protein Like 11 (OSBPl11), regulating triglyceride storage and sterol transport (Fig.…”

Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside

“…Additionally, increased ROS has been largely reported to be related to IR in animal models. HFD feeding has been reported to increase mitochondrial H 2 O 2 production and decrease redox-buffering capacity, oxidative capacity and ATP levels in the skeletal muscle of mice [ 55 , 56 , 57 , 58 ]. Nonetheless, blocking mt-ROS production or scavenging ROS has been found to be able to prevent IR [ 59 , 60 ].…”

Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age and Alzheimer’s Disease Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways

“…Beyond these specific regulatory switches at a global level, methionine oxidation may act as a sensor of cellular stress [1,2,[16][17][18][19][20][21][22][23] where protein incorporated MSox is accumulated, depleted, and regulated by the inducible system of Msr or related enzymes. The biological effects of Msr variation by knockout or knock-in have showed lifespan variation in flies related to antioxidant defense but results in mouse were equivocal, showing tissue specific mouse functions affected [24].…”