Dataset Information

Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC-MS metabolomics

ABSTRACT: Introduction: Obestatin is a controversial gastrointestinal peptide purported to have metabolic actions. Objectives: This study investigated whether treatment with a stable obestatin analogue (PEG-OB(Cys10, Cys13) changed plasma metabolite levels firstly in lean and subsequently in diet-induced obesity (DIO) C57BL6/J mice. Method: Untargeted LC-HRMS metabolomics experiments were carried out in ESI+ mode with plasma extracts from both groups of animals. Data were normalised, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. Result: In lean mice, 39 metabolites were significantly changed by obestatin treatment and the majority of these were increased, including various C16 and C18 moieties of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and monoacylglycerol, along with vitamin A, vitamin D3, tyrosine, acetylcarnitine and 2alpha-(hydroxymethyl)-5alpha-androstane-3beta,17beta-diol. Decreased concentrations of glycolithocholic acid, 3-dehydroteasterone and various phospholipids were observed. In DIO mice, 25 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater in DIO mice than in lean mice, and in contrast, the majority of metabolite changes were decreases. Four metabolites affected in both groups included glycolithocholic acid, and three different long-chain (C18) phospholipid molecules (phosphatidylethanolamine, platelet activating factor (PAF), and monoacylglycerol). Metabolites exclusively affected in DIO mice included various phosphatidylcholines, lysophosphatidylcholines and fatty acyls, as well as creatine and oxidised glutathione. Conclusion: This investigation demonstrates that obestatin treatment affects phospholipid turnover and influences lipid homeostasis, whilst providing convincing evidence that obestatin may be acting to ameliorate diet-induced impairments in lipid metabolism, and it may influence steroid, bile acid, PAF and glutathione metabolism.

INSTRUMENT(S): Orbitrap Elite (Thermo Scientific)

SUBMITTER: Elaine Cowan

PROVIDER: MTBLS334 | MetaboLights | 2017-07-25

REPOSITORIES: MetaboLights

ACCESS DATA

Publications

Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC-MS metabolomics.

Cowan Elaine E Kumar Praveen P Burch Kerry J KJ Grieve David J DJ Green Brian D BD Graham Stewart F SF

Metabolomics : Official journal of the Metabolomic Society 20160705

<h4>Introduction</h4>Obestatin is a controversial gastrointestinal peptide purported to have metabolic actions.<h4>Objectives</h4>This study investigated whether treatment with a stable obestatin analogue (PEG-OB(Cys<sup>10</sup>, Cys<sup>13</sup>)) changed plasma metabolite levels firstly in lean and subsequently in diet-induced obesity (DIO) C57BL6/J mice.<h4>Methods</h4>Untargeted LC-HRMS metabolomics experiments were carried out in ESI + mode with plasma extracts from both groups of animals. ...[more]

PMID: 27471436

Similar Datasets

Project description:Sen2013 - Phospholipid Synthesis in P.knowlesi The model describes the multiple phospholipid synthetic pathways in Plasmodium knowlesi. This model is described in the article: Kinetic modelling of phospholipid synthesis in Plasmodium knowlesi unravels crucial steps and relative importance of multiple pathways. Sen P, Vial HJ, Radulescu O. BMC Syst Biol 2013 Nov; 7(1): 123 Abstract: BACKGROUND: Plasmodium is the causal parasite of malaria, infectious disease responsible for the death of up to one million people each year. Glycerophospholipid and consequently membrane biosynthesis are essential for the survival of the parasite and are targeted by a new class of antimalarial drugs developed in our lab. In order to understand the highly redundant phospholipid synthethic pathways and eventual mechanism of resistance to various drugs, an organism specific kinetic model of these metabolic pathways need to be developed in Plasmodium species. RESULTS: Fluxomic data were used to build a quantitative kinetic model of glycerophospholipid pathways in Plasmodium knowlesi. In vitro incorporation dynamics of phospholipids unravels multiple synthetic pathways. A detailed metabolic network with values of the kinetic parameters (maximum rates and Michaelis constants) has been built. In order to obtain a global search in the parameter space, we have designed a hybrid, discrete and continuous, optimization method. Discrete parameters were used to sample the cone of admissible fluxes, whereas the continuous Michaelis and maximum rates constants were obtained by local minimization of an objective function.The model was used to predict the distribution of fluxes within the network of various metabolic precursors.The quantitative analysis was used to understand eventual links between different pathways. The major source of phosphatidylcholine (PC) is the CDP-choline Kennedy pathway.In silico knock-out experiments showed comparable importance of phosphoethanolamine-N-methyltransferase (PMT) and phosphatidylethanolamine-N-methyltransferase (PEMT) for PC synthesis.The flux values indicate that, major part of serine derived phosphatidylethanolamine (PE) is formed via serine decarboxylation, whereas major part of phosphatidylserine (PS) is formed by base-exchange reactions.Sensitivity analysis of CDP-choline pathway shows that the carrier-mediated choline entry into the parasite and the phosphocholine cytidylyltransferase reaction have the largest sensitivity coefficients in this pathway, but does not distinguish a reaction as an unique rate-limiting step. CONCLUSION: We provide a fully parametrized kinetic model for the multiple phospholipid synthetic pathways in P. knowlesi. This model has been used to clarify the relative importance of the various reactions in these metabolic pathways. Future work extensions of this modelling strategy will serve to elucidate the regulatory mechanisms governing the development of Plasmodium during its blood stages, as well as the mechanisms of action of drugs on membrane biosynthetic pathways and eventual mechanisms of resistance. This model is hosted on BioModels Database and identified by: BIOMD0000000495 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Dietary fatty acids have myriads of effects on human health and disease. Many of these effects are likely achieved by altering expression of genes. Several transcription factors have been shown to be responsive to fatty acids, including SREBP-1c, NF-kB, RXRs, LXRs, FXR, HNF4Î±, and PPARs. However, the relative importance of these transcription factors in regulation of gene expression by dietary fatty acids remains unclear. Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the acute effects of individual dietary fatty acids on hepatic gene expression in mice. The dietary interventions were performed in parallel in wild-type and PPARÎ±-/- mice, enabling the determination of the specific contribution of PPARÎ±. Depending on chain length and degree of saturation, dietary fatty acids caused a statistically significant change in expression of over 400 genes. Surprisingly, the far majority of genes regulated by dietary fatty acids in wild-type mice were unaltered in mice lacking PPARÎ±, indicating PPARÎ±-dependent regulation. We conclude that the effects of dietary fatty acids on hepatic gene expression are almost entirely mediated by PPARÎ±, indicating that PPARÎ± dominates fatty acid-dependent gene regulation in liver. Experiment Overall Design: 2-6 months old male pure bred wild-type (129S1/SvImJ) and PPARÎ± -/- (129S4/SvJae) mice were used. Experiment Overall Design: Wild-type and PPARÎ± -/- mice fasted for 4 hours received a single dose of 400 Âµl synthetic triglyceride (tridecanoin â C10:0, triolein â C18:1, trilinolein â C18:2, trilinolenin â C18:3, trieicosapentaenoin â C20:5 or tridocosahexaenoin â C22:6), the synthetic PPARÎ± agonists WY14643 or fenofibrate (400 Î¼l of 10 mg/ml in 0.5% carboxymethyl cellulose, CMC) or control (400 Î¼l of 0.5% CMC). 6 hours after gavage, mice were killed and livers extracted. Experiment Overall Design: (Please note: Experiments with C10:0, C18:2 and C18:3 were carried out a few months later than the rest of the treatments. Therefore there is a second set of control arrays â named control2 â which belong to these three treatment groups.) Experiment Overall Design: Liver total RNA from biological replicates was hybridized onto Affymetrix mouse genome 430 2.0 GeneChip arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

Dataset Information

Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC-MS metabolomics

Publications

Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC-MS metabolomics.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure