The epidemic of obesity leading to insulin resistance and eventually Type II diabetes has been well documented by the World Health Organization. This disease process originates with immune inflammation, and the specific components of the immune system that drive insulin resistance are just beginning to be unraveled. In particular, the adaptive immune system and especially T cells appear to play an important role. Both CD4 and CD8 T cell infiltrate adipose tissue in the obese state, and they are proposed to have opposing effects. CD8 T cells are proinflammatory, and accelerate the development of inflammatory macrophages, whereas CD4 T cells in the form of Th2 cells and T regulatory cells appear to suppress macrophage-mediated inflammation. This is a proposal to use mouse genetics to address these questions in novel ways. First, we will test genetically altered mice that lack difference T cell subsets for the progression to insulin resistance. This includes a strain of mice that lacks the ability to make anti-inflammatory Th2 cells. Second, we have discovered that T regulatory cells in the adipose tissue uniquely express a chemokine receptor that we propose allows them to localize to white fat. We propose to produce and test mice that lack this chemokine receptor specifically in regulatory cells, and with these mice determine whether a lack fat-localized T regulatory cells affect the high fat diet induced metabolic changes associated with progression to diabetes. Finally, we propose the novel hypothesis that Foxo transcription factors present a connection between the endocrine changes that occur as a result of obesity and the heightened inflammatory state of the immune system. Experiments are described that analyze the activity of Foxo transcription factors in various metabolic states, and furthermore how mice lacking Foxo transcription factors progress to insulin resistance under conditions of a high fat diet. These experiments will greatly enhance our knowledge of the interface between organismal metabolism and the immune system.

Public Health Relevance

The incidence of obesity leading to Type II diabetes has increased 3-fold since 1980 according to the World Health Organization. Progression to insulin resistance results from chronic inflammation occurring in the adipose tissue and mediated by macrophages. In this study we will show how the adaptive immune system in the form of T cells either promotes or suppresses this inflammation. These experiments will have important consequences for proposed treatments of patients exhibiting early metabolic changes associated with progression to diabetes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Lapham, Cheryl K
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University of California San Diego
Other Basic Sciences
Schools of Medicine
La Jolla
United States
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