Obesity threatens the health of children and adults in the U.S. based on its strong association with metabolic syndrome and Type 2 diabetes. The pro-inflammatory state induced by obesity has been directly linked to metabolic disease and is driven by inflammatory changes in adipose tissue. This is driven by adipose tissue leukocytes such as macrophages (ATM) and T cells that provide signals that can both positively and negatively influence nutrient metabolism by regulating adipocyte function. The mechanisms that govern the choice to either promote metabolic homeostasis or dysregulation are not well delineated. Revealing the mechanisms that govern the immune balance in adipose tissue will provide insight into new pathways that can be modified for new treatments for diabetes and other cardiometabolic disease. Antigen presenting cells (APCs) sit at the interface between innate and adaptive immune responses and associations between antigen presentation pathways and metabolic disease are well documented. We have discovered that direct communication between macrophages and CD4+ T cells in adipose tissue is a critical control point in the decision to generate regulatory/protective or immunostimulatory/pro-inflammatory signals. The identity of the signals that shape the adipose tissue immune response, when is regulation favored over immunity, which antigen presenting cells should be targeted for new therapeutics, and how these functions differ between metabolically healthy and unhealthy obese patients are unknown. This proposal will address these questions in pursuit of our long term goal of identifying the features of the adipose tissue immune system that contribute metabolic disease. This study will examine the hypothesis that ATM and adipose tissue dendritic cells (ATDC) control the phenotype of CD4+ T lymphocytes via APC function. This hypothesis is supported by our work in the prior funding cycle, but is enhanced by our recent unambiguous identification of ATDC, demonstration that ATM and ATDC differentially control metabolism and regulatory T cells, and identification of associations between MHCIIhi populations of ATMs in obese patients with diabetes. These findings drive the specific aims of the proposal which are: (1) To delineate the roles of ATMs and ATDCs in obesity-induced adipose tissue inflammation and T cell activation. (2) To assess the effects of weight loss on adipose tissue antigen presentation cell function. (3) To evaluate the association between ATM and ATDCs and diabetes status in obese humans. Completing our aims will have a significant impact on identifying the important communication pathways that shape the range of responses that can be generated by adipose tissue leukocytes. This is a required step in understanding how the adipose tissue immune system may be manipulated to either promote immune tolerance to obesity or block immunostimulatory signals. It will use innovative complementary studies to close the gap between our understanding of adipose tissue leukocyte biology in pre-clinical and clinical studies.

Public Health Relevance

Obesity-induced inflammation contributes to the development of insulin resistance and diabetes. This inflammation is caused by changes in the function and phenotype of immune cells found in adipose tissue. It is now recognized that immune cells in adipose tissue can not only provide signals that increase inflammation, but also provide beneficial signals that help preserve normal metabolism. This proposal will investigate how communication between several classes of immune cells in adipose tissue generate inflammation in obesity and may be harnessed to identify ways to blunt this inflammatory activation. We will study dendritic cells, macrophages and T cells in adipose tissue in mouse models of obesity and in obese humans. Results of this study could lead to a novel understanding of how inflammation triggers type 2 diabetes and identification of novel ways to modify communication between these cells to treat metabolic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK090262-07
Application #
9234511
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Abraham, Kristin M
Project Start
2011-01-11
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
7
Fiscal Year
2017
Total Cost
$348,750
Indirect Cost
$123,750
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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