No abstract

Selenoprotein P (SelenoP) functions as a plasma transporter of selenium (Se) from liver to other tissues via incorporation into multiple selenocysteine (Sec) residues. Selenocysteine lyase (Scly) is an intracellular enzyme that decomposes Sec into selenide, providing Se for the synthesis of new selenoproteins. Both SelenoP and Scly are mostly produced by the liver. Previous studies demonstrated that male mice lacking SelenoP (SelenoP KO) or Scly (Scly KO) had increased or decreased total hepatic Se, respectively. While SelenoP regulation by Se is well-studied, Scly regulation by Se has not been reported. We hypothesize that Scly is negatively regulated by Se levels, and that absence of SelenoP jeopardizes Scly-dependent Se recycling. Using in vitro and in vivo models, we unveiled a tissue-specific Se regulation of Scly gene expression. We also determined that SelenoP, a considered source of intracellular Se, affects Scly expression and activity in vitro but not in vivo, as in the absence of SelenoP, Scly levels and activity remain normal. We also showed that absence of SelenoP does not increase levels of transsulfuration pathway enzymes, which would result in available selenocompounds being decomposed by the actions of cystathionine γ-lyase (CGL or CTH) and cystathionine β-synthase (CBS). Instead, it affects levels of thioredoxin reductase 1 (Txnrd1), an enzyme that can reduce selenite to selenide to be used in selenoprotein production. This study evaluates a potential interplay between SelenoP and Scly, providing further insights into the regulation of selenium metabolism.

Selenium (Se) is an essential micronutrient known for its antioxidant properties and health benefits, attributed to its presence in selenoproteins as the amino acid, selenocysteine. Selenocysteine lyase (Scly) catalyzes hydrolysis of selenocysteine to selenide and alanine, facilitating re-utilization of Se for de novo selenoprotein synthesis. Previously, it was reported that male Scly−/− mice develop increased body weight and body fat composition, and altered lipid and carbohydrate metabolism, compared to wild type mice. Strikingly, females appeared to present with a less severe phenotype, suggesting the relationship between Scly and energy metabolism may be regulated in a sex-specific manner. Here, we report that while body weight and body fat gain occur in both male and female Scly−/− mice, strikingly, males are susceptible to developing glucose intolerance, whereas female Scly−/− mice are protected. Because Se is critical for male reproduction, we hypothesized that castration would attenuate the metabolic dysfunction observed in male Scly−/− mice by eliminating sequestration of Se in testes. We report that fasting serum insulin levels were significantly reduced in castrated males compared to controls, but islet area was unchanged between groups. Finally, both male and female Scly−/− mice exhibit reduced hypothalamic expression of selenoproteins S, M, and glutathione peroxidase 1.

No abstract

Skeletal muscle is responsible for the majority of glucose disposal following meals, and this is achieved by insulin-mediated trafficking of glucose transporter type 4 (GLUT4) to the cell membrane. The eight-protein exocyst trafficking complex facilitates targeted docking of membrane-bound vesicles, a process underlying the regulated delivery of fuel transporters. We previously demonstrated the role of exocyst subunit EXOC5 in insulin-stimulated GLUT4 exocytosis and glucose uptake in cultured rat skeletal myoblasts. However, the in vivo role of EXOC5 in skeletal muscle remains unclear. Using mice with inducible, skeletal-muscle-specific knockout of exocyst subunit EXOC5 ( Exoc5 -SMKO), we examined how muscle-specific disruption of the exocyst would affect glucose homeostasis in vivo . We found that both male and female Exoc5 -SMKO mice displayed elevated fasting glucose levels. Additionally, male Exoc5 -SMKO mice had impaired glucose tolerance and lower serum insulin levels. Using indirect calorimetry, we observed that male Exoc5 -SMKO mice have a reduced respiratory exchange ratio during the light period and lower energy expenditure. Using the hyperinsulinemic–euglycemic clamp method, we further showed that insulin-stimulated skeletal muscle glucose uptake is reduced in Exoc5 -SMKO males compared with wild-type controls. Overall, our findings indicate that EXOC5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle and regulate glucose homeostasis in vivo .