Dataset Information

Metabolomic Diagnosis in Horse

ABSTRACT: In this project we will investigate the feasibility of metabolomics and to characterize the diversity of metabotypes in the horse, towards discovery of markers and pathways associated with obesity and insulin resistance in the equine model. The collaborative team of researchers assembled for this work have identified horses severely affected with Equine Metabolic syndrome, often characterized by obesity and hyperinsulinemia. These animals are all from the Arabian breed, to control for some genetic background. Horses are age, sex and farm of residence matched with a control animal whenever possible. Carefully controlled collection protocols were utilized to ensure minimal variability in sample age and quality. Blood plasma is submitted for both global LC-MS analysis through the SECIM core facilities. This discovery-based approach will begin to generate new targets for the development of novel therapeutic interventions for the treatment and prevention of obesity, type-2 diabetes as well as related secondary conditions in both humans and horses. Finally, as the first dataset of its kind in the horse, we may also be able to highlight promising new biomarkers for veterinary diagnostic use.

ORGANISM(S): Horse Equus Caballus

TISSUE(S): Blood

SUBMITTER: Samantha Brooks

PROVIDER: ST000244 | MetabolomicsWorkbench | Tue Oct 13 00:00:00 BST 2015

REPOSITORIES: MetabolomicsWorkbench

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

Project description:Sanchez2017 - Inflammatory responses during acute hyperinsulinemia This model is described in the article: The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study Mariana E. Martinez-Sanchez, Marcia Hiriart, Elena R. Alvarez-Buylla BMC Systems Biology Abstract: Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGF? producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGF? in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment. This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases. This model is hosted on BioModels Database and identified by: MODEL1606020000. 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.

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Metabolomic Diagnosis in Horse

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