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

Mori MA, Liu M, Bezy O, Almind K, Shapiro H, Kasif S, Kahn CR - Diabetes (2010)

Bottom Line: This was accompanied by increased T-cell and macrophage infiltration.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.

View Article: PubMed Central - PubMed

Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

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.

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Schematic model illustrating the potential causes and consequences related to the different repertoire of immune cells in adipose tissue of B6 and 129 mice. Solid arrows, secretion; dashed arrows, migration; dotted arrows, migration/differentiation.
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Figure 7: Schematic model illustrating the potential causes and consequences related to the different repertoire of immune cells in adipose tissue of B6 and 129 mice. Solid arrows, secretion; dashed arrows, migration; dotted arrows, migration/differentiation.

Mentions: Although a relationship between obesity and inflammation in fat has been previously observed, in most cases these inflammatory changes have been viewed as being secondary to obesity. Our data, comparing diabetes-prone B6 mouse and diabetes-resistant 129 mouse at 6 weeks of age, show alterations in the inflammatory process in adipose tissue even before differences in metabolic parameters can be detected. Thus, B6 mice exhibit increased expression of the T-cell chemokines SDF1α and CCL5/RANTES and an increased number of T-cells in the fat tissue. These differences are associated with higher IFNγ and CD80 levels in the B6 mice—both molecules are known to participate in T-cell function and activation (25) (summarized in the model shown in Fig. 7).


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

Mori MA, Liu M, Bezy O, Almind K, Shapiro H, Kasif S, Kahn CR - Diabetes (2010)

Schematic model illustrating the potential causes and consequences related to the different repertoire of immune cells in adipose tissue of B6 and 129 mice. Solid arrows, secretion; dashed arrows, migration; dotted arrows, migration/differentiation.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2963557&req=5

Figure 7: Schematic model illustrating the potential causes and consequences related to the different repertoire of immune cells in adipose tissue of B6 and 129 mice. Solid arrows, secretion; dashed arrows, migration; dotted arrows, migration/differentiation.
Mentions: Although a relationship between obesity and inflammation in fat has been previously observed, in most cases these inflammatory changes have been viewed as being secondary to obesity. Our data, comparing diabetes-prone B6 mouse and diabetes-resistant 129 mouse at 6 weeks of age, show alterations in the inflammatory process in adipose tissue even before differences in metabolic parameters can be detected. Thus, B6 mice exhibit increased expression of the T-cell chemokines SDF1α and CCL5/RANTES and an increased number of T-cells in the fat tissue. These differences are associated with higher IFNγ and CD80 levels in the B6 mice—both molecules are known to participate in T-cell function and activation (25) (summarized in the model shown in Fig. 7).

Bottom Line: This was accompanied by increased T-cell and macrophage infiltration.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.

View Article: PubMed Central - PubMed

Affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus