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


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.
Mori
Marcelo A
MA
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
Liu
Manway
M
Bezy
Olivier
O
Almind
Katrine
K
Shapiro
Hagit
H
Kasif
Simon
S
Kahn
C Ronald
CR
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology; D018450:Disease Progression; D002149:Energy Intake; D004734:Energy Metabolism; D004777:Environment; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008659:Metabolic Diseases / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D050177:Overweight / Q000453:epidemiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D014944:World Health Organization