Robust T cell mediated immune responses are key components of protection from infection and certain cancers. Emerging evidence suggests that, apart from increased incidence of cardiovascular diseases and cancers, obesity also compromises T cell dependent immune-surveillance mechanisms in mice with increased risk and severity of infections. It is recognized that thymic export of T cells establishes the size and diversity of human naive T cell repertoire. Intriguingly, by middle age, thymus undergoes a process of involution characterized by reduced naive T cell production together with replacement of thymic space with adipocytes. Dietary-obesity is known to increase lipid deposition in several ectopic sites such as muscle, liver and compromise organ function. Similarly, we have shown that obesity in mice exacerbates the mechanisms that promote deposition of ectopic lipid-bearing adipocyte in thymus and reduces generation of naive T cells from thymus. Based on our data from mouse models that obesity restricts T cell receptor (TCR) repertoire diversity and preliminary findings in obese humans, we propose to test the hypothesis that, obesity accelerates immunosenescence and excess weight-loss can rescue loss of thymopoiesis and restriction of T cell repertoire diversity and function in humans. The overall goal of this project is to assess specific hypotheses and predictions about the relationship between obesity and immune system - in particular, thymopoiesis and T cell-mediated immunity - with implications for understanding the mechanisms whereby weight-loss might enhance immune- surveillance in humans. Therefore, we propose to study the impact of obesity and subsequent weight-loss through bariatric surgery and caloric restriction on functional thymic content, thymopoiesis, T cell function and TCR diversity in humans. We propose three specific aims, 1) To test the prediction that obesity increases ectopic adipocyte development in thymus. 2) To test the prediction that obesity lowers thymopoiesis and compromises T cell function. 3) To test the prediction that obesity-induced reduction in functional thymic space, thymopoiesis, and aberrant immune function can be rescued by weight-loss therapy.

Public Health Relevance

Obesity is associated with increased risk and severity of infections and cancers. T cell mediated immune- surveillance is vital for protection against pathogens as well as certain cancers. To date, no studies in humans have evaluated whether obesity impacts the protective T cell immune function. The overall goal of this project is to determine the mechanism of immune dysfunction in obesity and investigate the impact of distinct weight loss treatments on reversing the decline in immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK090556-04
Application #
8753313
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Abraham, Kristin M
Project Start
2011-04-01
Project End
2015-03-31
Budget Start
2014-01-10
Budget End
2014-03-31
Support Year
Fiscal Year
2013
Total Cost
$371,595
Indirect Cost
$138,130
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Kursawe, Romy; Dixit, Vishwa D; Scherer, Philipp E et al. (2016) A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents. Diabetes 65:610-8
Spadaro, Olga; Goldberg, Emily L; Camell, Christina D et al. (2016) Growth Hormone Receptor Deficiency Protects against Age-Related NLRP3 Inflammasome Activation and Immune Senescence. Cell Rep 14:1571-80
Goldberg, Emily L; Dixit, Vishwa Deep (2015) Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev 265:63-74
Youm, Yun-Hee; Nguyen, Kim Y; Grant, Ryan W et al. (2015) The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21:263-9
Camell, Christina D; Nguyen, Kim Y; Jurczak, Michael J et al. (2015) Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity. J Biol Chem 290:29402-13
Grant, Ryan W; Dixit, Vishwa Deep (2015) Adipose tissue as an immunological organ. Obesity (Silver Spring) 23:512-8
Camell, Christina; Goldberg, Emily; Dixit, Vishwa Deep (2015) Regulation of Nlrp3 inflammasome by dietary metabolites. Semin Immunol 27:334-42
Grant, Ryan; Nguyen, Kim Y; Ravussin, Anthony et al. (2014) Inactivation of C/ebp homologous protein-driven immune-metabolic interactions exacerbate obesity and adipose tissue leukocytosis. J Biol Chem 289:14045-55
Dixit, Vishwa Deep (2013) Adipose tissue macrophages are innate to the immunological awareness of adipose tissue. Diabetes 62:2656-8

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