Cancer Prevention Program

Adipose Tissue Inflammation in the Etiology of Obesity-associated Chronic Disease

PI: Mario Kratz, PhD

Obesity is associated with chronic low-grade systemic inflammation. A large number of studies have found that an increased body mass index correlates with increased plasma concentrations of inflammatory cytokines and acute phase proteins. This systemic inflammation is associated with insulin resistance leading to type 2 diabetes mellitus as well as increased risk of cardiovascular disease and certain types of cancer. Recent evidence suggests that this systemic inflammation is caused, at least in part, by adipose tissue inflammation. Experiments in mouse models of obesity suggest that an increase in body fat mass is associated with increased infiltration of adipose tissue with macrophages, T cells, and other leukocytes, and changes in the phenotypes of these cells in adipose tissue. It is unclear whether this applies to humans, and whether the adipose tissue infiltration of leukocytes contributes to systemic infiltration, insulin resistance, and the increased risk of cardiovascular disease and certain types of cancer associated with obesity. We are currently conducting a number of clinical studies to investigate the relationship between adipose tissue leukocytes populations and systemic inflammation, insulin resistance, and the dyslipidemia that is known to be associated with increased body fat mass. Methods employed to study adipose tissue inflammation include flow cytometry to immunophenotypically characterize tissue leukocytes, fluorescence-activated cell sorting (FACS), immunohistochemistry, sequencing of the T cell receptor repertoire, and gene expression analyses of whole tissue or sorted cell populations.

Currently ongoing studies include an American Diabetes Association-funded clinical study to characterize the relationship between specific myeloid cell populations and insulin resistance, and a National Cancer Institute-funded study to identify the cellular source for the key estrogen-synthesizing enzyme aromatase in adipose tissue. Our long-term goal will be to identify the factors that contribute to adipose tissue inflammation, and to develop strategies to prevent or treat this condition that may be an important etiologic factor in the development of chronic disease in man, including type 2 diabetes, cardiovascular disease, and certain types of obesity-associated cancer.