Adipose tissue inflammation is associated with immune dysfunction during influenza virus infection.

摘要

Adipose tissue in the obese state expresses increased concentrations of inflammatory mediators and has an increased number of macrophages and T lymphocytes. This raises questions about the role that adipose tissue plays during an infectious disease. This dissertation describes research in diet-induced obese mice that (1) provides a timeline of changes in body composition, hormonal and metabolic alterations, and the onset of inflammation in the liver and three adipose tissue depots; and (2) demonstrates that during an infectious disease, distant adipose tissue depots undergo changes in their inflammatory state and number of leukocytes. A third, conceptually distinct part of this dissertation is the study of a mechanism linking preadipocyte proliferation with differentiation.;The differentiation of preadipocytes contributes to increased adipose tissue mass through increased capacity to store triacylglycerol. Differentiation-induced 3T3-L1 preadipocytes undergo several rounds of mitotic clonal expansion while concurrently initiating a cascade of transcription factor expression that culminates in the adipocyte phenotype. We demonstrated that G1 of the cell cycle and the initiation of differentiation are functionally linked by the interaction of hypophosphorylated Rb and C/EBPbeta.;In order to establish a timeline of the development of inflammation in diet-induced obesity, weanling C57BL/6 mice were fed either a low-fat or a high-fat diet for 16 weeks. Our data show that the inflammatory state in adipose tissue is depot-specific, and occurs prior to the development of liver steatosis, and increased fasting serum leptin and insulin concentrations.;Previous work in our laboratory demonstrated that compared to lean mice, diet-induced obese mice have higher morbidity and mortality after influenza virus infection. We demonstrate that during influenza A/PR/8/34 virus infection, relative to lean mice, adipose tissues in obese mice have a greater pro-inflammatory cytokine and chemokine gene expression, with a decrease in the number of macrophages and T lymphocytes in the gonadal adipose tissue depot.;Taken together, our studies demonstrate that obesity can have a profound influence on the immune response to an infectious disease and that adipose tissue itself may be a major component of the dysregulated immune response during influenza infection.