Effect of Physical Exercise and Genetic Background on Glucose Homeostasis and Liver/Muscle Proteomes in Mice.

We compared the parameters related to glucose homeostasis, and liver and muscle proteomes in fluorosis-susceptible (A/J; S) and fluorosis-resistant (129P3/J; R) mice in response to fluoride (F) exposure and exercise. Ninety male mice (45 R-mice and 45 S-mice) were randomized into three groups: (SI; RI) No-F, No-Exercise, (SII; RII) 50 ppm F, No-Exercise, (SIII; RIII) 50 ppm F, Exercise. Overall, mean F concentrations in the plasma and femur were significantly higher in R-mice compared with S-mice. In R-mice, exercise resulted in an increase in F accumulation in the femur. In S-mice, the mean plasma glucose level was significantly higher in Group II compared with Groups I and III. There was an increase in liver proteins involved in energy flux and antioxidant enzymes in non-exercise groups (I, II) of S-mice in comparison with the corresponding groups of R-mice. The results also showed a decrease in muscle protein expression in Group I S-mice compared with their R-mice counterparts. In conclusion, the findings suggest an increased state of oxidative stress in fluorosis-susceptible mice that might be exacerbated by the treatment with F. In addition, fluorosis-susceptible mice have plasma glucose levels higher than fluorosis-resistant mice on exposure to F, and this is not affected by exercise

Metabolic effect of low fluoride levels in the islets of NOD mice: integrative morphological, immunohistochemical, and proteomic analyses

Fluoride (F) has been widely used to control dental caries, and studies suggest beneficial effects against diabetes when a low dose of F is added to the drinking water (10 mgF/L). Objectives: This study evaluated metabolic changes in pancreatic islets of NOD mice exposed to low doses of F and the main pathways altered by the treatment. Methodology: In total, 42 female NOD mice were randomly divided into two groups, considering the concentration of F administered in the drinking water for 14 weeks: 0 or 10 mgF/L. After the experimental period, the pancreas was collected for morphological and immunohistochemical analysis, and the islets for proteomic analysis. Results: In the morphological and immunohistochemical analysis, no significant differences were found in the percentage of cells labelled for insulin, glucagon, and acetylated histone H3, although the treated group had higher percentages than the control group. Moreover, no significant differences were found for the mean percentages of pancreatic areas occupied by islets and for the pancreatic inflammatory infiltrate between the control and treated groups. Proteomic analysis showed large increases in histones H3 and, to a lesser extent, in histone acetyltransferases, concomitant with a decrease in enzymes involved in the formation of acetyl-CoA, besides many changes in proteins involved in several metabolic pathways, especially energy metabolism. The conjunction analysis of these data showed an attempt by the organism to maintain protein synthesis in the islets, even with the dramatic changes in energy metabolism. Conclusion: Our data suggests epigenetic alterations in the islets of NOD mice exposed to F levels comparable to those found in public supply water consumed by humans

Efeito do fluoreto em parâmetros relacionados à homeostasia da glicose em camundongos NOD: uso da análise proteômica do fígado e músculo gastrocnêmio para revelar os mecanismos envolvidos

Water fluoridation is an important public health measure for the control of dental caries. Recent animal studies have shown that low doses of fluoride (F) in the drinking water, similar to those found in public water supplies, increase insulin sensitivity and reduce blood glucose. In the present study we evaluated the effects of low-level F exposure through the drinking water on glucose homeostasis in female NOD mice. Seventy-two 6-week mice were randomly divided into 2 groups according to the concentration of F in the drinking water (0-control, or 10 mg/L) they received for 14 weeks. After the experimental period the blood was collected for analyses of plasma F, glucose and insulin. Liver and gastrocnemius muscle were collected for proteomic analysis. Plasma F concentrations were significantly higher in the F-treated than in the control group. Despite treatment with fluoridated water reduced plasma levels glucose by 20% compared to control, no significant differences were found between the groups for plasma glucose and insulin. In the muscle, treatment with fluoridated water increased the expression of proteins related to muscle contraction, while in the liver, there was an increase in expression of antioxidant proteins and in proteins related to carboxylic acid metabolic process. Remarkably, phosphoenolpyruvate carboxykinase (PEPCK) was found exclusively in the liver of control mice. The reduction in PEPCK, a positive regulator of gluconeogenesis, thus increasing glucose uptake, might be a probable mechanism to explain the anti-diabetic effects of low doses of F, which should be evaluated in further studies.A fluoretação da água é uma importante medida de saúde pública para o controle da cárie dentária. Estudos recentes em animais mostraram que baixas doses de flúor (F) na água potável, semelhantes às encontradas no abastecimento público de água, aumentam a sensibilidade à insulina e reduzem a glicose no sangue. No presente estudo, avaliamos os efeitos da exposição de baixo nível de F através da água potável na homeostase da glicose em camundongas NOD fêmeas. Setenta e dois ratos de 6 semanas foram divididos aleatoriamente em 2 grupos, de acordo com a concentração de F na água potável (controle 0 ou 10 mg / L) que receberam por 14 semanas. Após o período experimental, o sangue foi coletado para análises de plasma F, glicose e insulina. Fígado e músculo gastrocnêmio foram coletados para análise proteômica. As concentrações plasmáticas de F foram significativamente maiores no grupo tratado com F do que no grupo controle. Apesar do tratamento com água fluoretada ter reduzido os níveis plasmáticos de glicose em 20% em comparação ao controle, não foram encontradas diferenças significativas entre os grupos para glicose plasmática e insulina. No músculo, o tratamento com água fluoretada aumentou a expressão de proteínas relacionadas à contração muscular, enquanto no fígado houve aumento na expressão de proteínas antioxidantes e de proteínas relacionadas ao processo metabólico do ácido carboxílico. Notavelmente, a fosfoenolpiruvato carboxiquinase (PEPCK) foi encontrada exclusivamente no fígado de camundongos controle. A redução do PEPCK, um regulador positivo da gliconeogênese, aumentando assim a captação de glicose, pode ser um mecanismo provável para explicar os efeitos antidiabéticos de baixas doses de F, que devem ser avaliadas em estudos futuros