Obesity predisposes to both systemic and adipose-tissue inflammation that is associated with the development of metabolic syndrome, including insulin resistance leading to type 2 diabetes. In obese adipose tissue, there is an influx of immune cells, particularly macrophages and lymphocytes, which secrete inflammatory cytokines that promote this phenotype. T lymphocytes (T cells) have an early and critical role in obesity-induced inflammation, as adipose-resident T cells in obesity are activated and undergo a shift in subset differentiation, leading to increased inflammatory effector T cells (Teff) and decreased suppressive regulatory T cells (Treg), which precedes the recruitment of macrophages into adipose tissue. Understanding how T cells are differentiated and activated in obesity is a critically important step in understanding the mechanism of obesity-driven inflammation. Activation of T cells results in an increased metabolic demand to fuel T cell proliferation and cytokine production. Inflammatory Teff cells meet this increased metabolic demand by upregulating glucose uptake and metabolism, whereas Treg cells utilize a distinct metabolic program of lipid oxidation. These metabolic programs are essential for each subset; therefore, identification of factors that promote glucose metabolism may alter the Teff/Treg balance and mediate obesity-associated inflammation. We have identified a novel link between nutritional status and T cell activation and metabolism through the adipokine leptin. Leptin is secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin is well-known for its ability to regulate food intake and whole body metabolism, but it is also a pro- inflammatory cytokine, with important effects on immune cell number and function. We have now shown that leptin promotes T cell glucose metabolism to fuel Teff activation. Therefore, while T cell activation in obesity is likely altered via multiple mechanisms, increased circulating leptin may be a key factor. The objective of this proposal is to identify mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes. We hypothesize that obesity-associated hyperleptinemia directly promotes T cell glycolytic metabolism to drive T cell inflammation. To test our hypothesis we propose the following Specific Aims: (1) Identify the role of leptin in Teff versus Treg differentiation and metabolism and in the development of insulin resistance in obesity. (2) Examine signaling pathways by which leptin may mediate changes to T cell differentiation and metabolism to promote inflammation and insulin resistance in obesity. At the completion of this project, we will better understand the role of leptin in linking nutritional status with immune cell metabolism and differentiation in obesity. Understanding mechanisms by which T cells respond to obesity may identify novel markers and targets for the treatment of diabetes and metabolic disease.

Public Health Relevance

Obesity is associated with inflammation which predisposes to metabolic syndrome and the associated increased risk of type 2 diabetes. T cells have an early and critical role in obesity associated inflammation. Here, we will identify molecular mechanisms by which T cells become activated and contribute to metabolic disease pathogenesis in obesity. Identification of such mechanisms may offer novel therapeutic targets for the treatment of type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK106090-01
Application #
8942057
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Abraham, Kristin M
Project Start
2015-08-21
Project End
2020-06-30
Budget Start
2015-08-21
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$357,750
Indirect Cost
$132,750
Name
Duke University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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