Dataset Information

Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes.

ABSTRACT: Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1(-/-) mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy.

SUBMITTER: van Diepen JA

PROVIDER: S-EPMC4773925 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes.

van Diepen Janna A JA Jansen Patrick A PA Ballak Dov B DB Hijmans Anneke A Rutjes Floris P J T FP Tack Cees J CJ Netea Mihai G MG Schalkwijk Joost J Stienstra Rinke R

Scientific reports 20160302

Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In ...[more]

PMID: 26932716

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Project description:BackgroundThe animal model is a key tool in quantitative genetics and has been used extensively to estimate fundamental parameters, such as additive genetic variance or heritability. An implicit assumption of animal models is that all founder individuals derive from a single population. This assumption is commonly violated, for instance in crossbred livestock or when a meta-population is split into genetically differentiated subpopulations. Ignoring that base populations are genetically heterogeneous and thus split into different 'genetic groups' may lead to biased parameter estimates, especially for additive genetic variance. To avoid such biases, genetic group animal models, which account for the presence of more than one genetic group, have been proposed. Unfortunately, the method to date is only computationally feasible when the breeding values of the groups are allowed to differ in their means, but not in their variances.ResultsWe present an extension of the animal model that permits estimation of group-specific additive genetic variances. This is achieved by employing group-specific relatedness matrices for the breeding value components to different genetic groups. We derive these matrices by decomposing the full relatedness matrix via the generalized Cholesky decomposition, and by scaling the respective matrix components for each group. We propose a computationally convenient approximation for the matrix component that encodes for the Mendelian sampling variance, and show that this approximation is not critical. In addition, we explain why segregation variances are often negligible when analyzing the complex polygenic traits that are frequently the focus of evolutionary ecologists and animal breeders. Simulations and an example from an insular meta-population of house sparrows in Norway with three distinct genetic groups illustrate that the method is successful in estimating group-specific additive genetic variances, and that segregation variances are indeed negligible in the empirical example.ConclusionsQuantifying differences in additive genetic variance within and among populations is of major biological interest in ecology, evolution, and animal and plant breeding. The proposed method allows to estimate such differences for subpopulations that form a connected set of populations, and may thus also be useful to study temporal or spatial variation of additive genetic variances.

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Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes.

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Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes.

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