Dataset Information

A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease.

ABSTRACT:

Objective

Type 2 diabetes and obesity are increasingly affecting human populations around the world. Our goal was to identify early molecular signatures predicting genetic risk to these metabolic diseases using two strains of mice that differ greatly in disease susceptibility.

Research design and methods

We integrated metabolic characterization, gene expression, protein-protein interaction networks, RT-PCR, and flow cytometry analyses of adipose, skeletal muscle, and liver tissue of diabetes-prone C57BL/6NTac (B6) mice and diabetes-resistant 129S6/SvEvTac (129) mice at 6 weeks and 6 months of age.

Results

At 6 weeks of age, B6 mice were metabolically indistinguishable from 129 mice, however, adipose tissue showed a consistent gene expression signature that differentiated between the strains. In particular, immune system gene networks and inflammatory biomarkers were upregulated in adipose tissue of B6 mice, despite a low normal fat mass. This was accompanied by increased T-cell and macrophage infiltration. The expression of the same networks and biomarkers, particularly those related to T-cells, further increased in adipose tissue of B6 mice, but only minimally in 129 mice, in response to weight gain promoted by age or high-fat diet, further exacerbating the differences between strains.

Conclusions

Insulin resistance in mice with differential susceptibility to diabetes and metabolic syndrome is preceded by differences in the inflammatory response of adipose tissue. This phenomenon may serve as an early indicator of disease and contribute to disease susceptibility and progression.

SUBMITTER: Mori MA

PROVIDER: S-EPMC2963557 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Publications

A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease.

Mori Marcelo A MA Liu Manway M Bezy Olivier O Almind Katrine K Shapiro Hagit H Kasif Simon S Kahn C Ronald CR

Diabetes 20100816 11

<h4>Objective</h4>Type 2 diabetes and obesity are increasingly affecting human populations around the world. Our goal was to identify early molecular signatures predicting genetic risk to these metabolic diseases using two strains of mice that differ greatly in disease susceptibility.<h4>Research design and methods</h4>We integrated metabolic characterization, gene expression, protein-protein interaction networks, RT-PCR, and flow cytometry analyses of adipose, skeletal muscle, and liver tissue ...[more]

PMID: 20713682

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Project description:Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different "omics," clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental "virtual" liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal-fetal-placental immune interactions in preeclampsia. The description of these novel pathways in the "molecular phase" of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.

Dataset Information

A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease.

Objective

Research design and methods

Results

Conclusions

Publications

A systems biology approach identifies inflammatory abnormalities between mouse strains prior to development of metabolic disease.

Similar Datasets

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