Effects of body weight and alcohol consumption on insulin sensitivity

<p>Abstract</p> <p>Background</p> <p>Obesity is a risk factor for the development of insulin resistance, which can eventually lead to type-2 diabetes. Alcohol consumption is a protective factor against insulin resistance, and thus protects against the development of type-2 diabetes. The mechanism by which alcohol protects against the development of type-2 diabetes is not well known. To determine the mechanism by which alcohol improves insulin sensitivity, we fed water or alcohol to lean, control, and obese mice. The aim of this study was to determine whether alcohol consumption and body weights affect overlapping metabolic pathways and to identify specific target genes that are regulated in these pathways.</p> <p>Method</p> <p>Adipose tissue dysfunction has been associated with the development of type-2 diabetes. We assessed possible gene expression alterations in epididymal white adipose tissue (WAT). We obtained WAT from mice fed a calorie restricted (CR), low fat (LF Control) or high fat (HF) diets and either water or 20% ethanol in the drinking water. We screened the expression of genes related to the regulation of energy homeostasis and insulin regulation using a gene array composed of 384 genes.</p> <p>Results</p> <p>Obesity induced insulin resistance and calorie restriction and alcohol improved insulin sensitivity. The insulin resistance in obese mice was associated with the increased expression of inflammatory markers Cd68, Il-6 and Il-1α; in contrast, most of these genes were down-regulated in CR mice. Anti-inflammatory factors such as Il-10 and adrenergic beta receptor kinase 1 (Adrbk1) were decreased in obese mice and increased by CR and alcohol. Also, we report a direct correlation between body weight and the expression of the following genes: Kcnj11 (potassium inwardly-rectifying channel, subfamily J, member 11), Lpin2 (lipin2), and Dusp9 (dual-specificity MAP kinase phosphatase 9).</p> <p>Conclusion</p> <p>We show that alcohol consumption increased insulin sensitivity. Additionally, alterations in insulin sensitivity related with obesity were coupled with alterations in inflammatory genes. We provide evidence that alcohol may improve insulin sensitivity by up-regulating anti-inflammatory genes. Moreover, we have indentified potential gene targets in energy metabolic pathways and signal transducers that may contribute to obesity-related insulin resistance as well as calorie restriction and alcohol-induced insulin sensitivity.</p

Cardiovascular changes in atherosclerotic ApoE-deficient mice exposed to Co60 (γ) radiation.

BACKGROUND: There is evidence for a role of ionizing radiation in cardiovascular diseases. The goal of this work was to identify changes in oxidative and nitrative stress pathways and the status of the endothelinergic system during progression of atherosclerosis in ApoE-deficient mice after single and repeated exposure to ionizing radiation. METHODS AND RESULTS: B6.129P2-ApoE tmlUnc mice on a low-fat diet were acutely exposed (whole body) to Co60 (γ) (single dose 0, 0.5, and 2 Gy) at a dose rate of 36.32 cGy/min, or repeatedly (cumulative dose 0 and 2 Gy) at a dose-rate of 0.1 cGy/min for 5 d/wk, over a period of 4 weeks. Biological endpoints were investigated after 3-6 months of recovery post-radiation. The nitrative stress marker 3-nitrotyrosine and the vasoregulator peptides endothelin-1 and endothelin-3 in plasma were increased (p<0.05) in a dose-dependent manner 3-6 months after acute or chronic exposure to radiation. The oxidative stress marker 8-isoprostane was not affected by radiation, while plasma 8-hydroxydeoxyguanosine and L-3,4-dihydroxyphenylalanine decreased (p<0.05) after treatment. At 2Gy radiation dose, serum cholesterol was increased (p = 0.008) relative to controls. Percent lesion area increased (p = 0.005) with age of animal, but not with radiation treatment. CONCLUSIONS: Our observations are consistent with persistent nitrative stress and activation of the endothelinergic system in ApoE-/- mice after low-level ionizing radiation exposures. These mechanisms are known factors in the progression of atherosclerosis and other cardiovascular diseases

Marker of protein nitration.

<p>Plasma levels of 3-nitrotyrosine (A, B) and 3-nitrotyrosine/L-Dopa ratio (C, D) in Apo-E−/− mice following acute (A, C) or chronic (B, D) radiation exposure. Mean ± SEM. Acute, 0 (n = 3), 0.5 Gy (n = 8), 2 Gy (n = 4). Chronic, 0 (n = 4), 2 Gy (n = 4). 3-nitrotyrosine: Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors, <i>Dose</i> main effect, p = 0.004. *Tukey test, 0 vs 2 Gy, p<0.05. 3-nitrotyrosine/L-DOPA: Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors, <i>Dose</i> X <i>Time,</i> p = 0.025. *Tukey test, 0 vs 2 Gy, p<0.05. +Tukey test, acute vs chronic, p<0.05.</p

Marker of DNA oxidation.

<p>Plasma levels of 8-hydroxy-deoxyguanosine in Apo-E−/− mice following (A) acute (B) chronic radiation exposure. Mean ± SEM. Acute, 0 (n = 3), 0.5 Gy (n = 8), 2 Gy (n = 4). Chronic, 0 (n = 4), 2 Gy (n = 4). Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors. <i>Dose x Time</i> interaction, p = 0.047. * Tukey test, <i>Dose</i> within chronic, 0 vs 2 Gy, p<0.05.</p

Blood cholesterol.

<p>Apo-E−/− mice serum cholesterol levels after acute (A) and chronic (B) exposure to radiation. Mean ± SEM. Acute, 0 (n = 15), 0.5 Gy (n = 15), 2 Gy (n = 15). Chronic, 0 (n = 15), 2 Gy (n = 15). One-way ANOVA on acute exposure (0, 0.5, 2 Gy), p = 0.011. +Tukey, 0 vs 0.5 Gy, p<0.05. Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors, <i>Dose</i> main effect, p = 0.008. *Tukey test, 0 vs 2 Gy, p<0.05.</p

Marker of nitric oxide.

<p>Effect of acute (A) and chronic (B) radiation exposure on circulating nitrite levels in Apo-E−/− mice. Mean ± SEM. Acute, 0 (n = 4), 0.5 Gy (n = 7), 2 Gy (n = 3). Chronic, 0 (n = 4), 2 Gy (n = 3).</p

Vasoconstrictor peptides.

<p>Vasoconstrictor peptides BET-1 (A, B), ET-1 (C, D), ET-2 (E, F), ET-3 (G, H) and the ET-1/ET-3 ratio (I, J) in Apo-E−/− mice after acute (A, C, E, G, I) and chronic (B, D, F, H, J) radiation exposure. Mean ± SEM. Acute, 0 (n = 3), 0.5 Gy (n = 5), 2 Gy (n = 5). Chronic, 0 (n = 6), 2 Gy (n = 5). Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors. ET-1: <i>Dose</i> main effect, p = 0.016. *Tukey test, 0 vs 2 Gy, p<0.05. ET-3: <i>Dose</i> main effect, p = 0.020. *Tukey test, 0 vs 2 Gy, p<0.05. ET-1/ET-3: <i>Time</i> main effect, p = 0.032. *Tukey test, acute vs chronic, p<0.05.</p

Marker of lipid oxidation.

<p>Plasma levels of 8–isoprostane in Apo-E−/− mice following acute (A) and chronic (B) radiation exposure. Mean ± SEM. Acute, 0 (n = 3), 0.5 Gy (n = 4), 2 Gy (n = 4). Chronic, 0 (n = 3), 2 Gy (n = 4).</p

Atherosclerosis plaques.

<p>Sections of the orifices of the coronary arteries marking the start of the ascending arch in a 5-month old control ApoE−/− mouse (A) and an ApoE−/− mouse following chronic radiation exposure (B). Percent lesion area profiles for acute (C) and chronic (D) radiation exposure. Mean ± SEM. Acute, 0 (n = 15), 0.5 Gy (n = 15), 2 Gy (n = 15). Chronic, 0 (n = 15), 2 Gy (n = 15). Two-way ANOVA with <i>Dose</i> (0, 2 Gy) and <i>Time</i> (acute, chronic) as factors, <i>Time</i> main effect, p = 0.005. *Tukey test, acute vs chronic, p<0.05.</p