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 #
5R01DK090556-05
Application #
8636459
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
2014-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2014
Total Cost
$435,972
Indirect Cost
$174,127
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Dixit, Vishwa Deep (2013) Nlrp3 inflammasome activation in type 2 diabetes: is it clinically relevant? Diabetes 62:22-4
Youm, Yun-Hee; Grant, Ryan W; McCabe, Laura R et al. (2013) Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18:519-32
Grant, Ryan; Youm, Yun-Hee; Ravussin, Anthony et al. (2013) Quantification of adipose tissue leukocytosis in obesity. Methods Mol Biol 1040:195-209
De Guzman, Jennifer M; Ku, Ginger; Fahey, Ryan et al. (2013) Chronic caloric restriction partially protects against age-related alteration in serum metabolome. Age (Dordr) 35:1091-104
Dixit, Vishwa Deep (2013) Adipose tissue macrophages are innate to the immunological awareness of adipose tissue. Diabetes 62:2656-8
Youm, Yun-Hee; Adijiang, Ayinuer; Vandanmagsar, Bolormaa et al. (2011) Elimination of the NLRP3-ASC inflammasome protects against chronic obesity-induced pancreatic damage. Endocrinology 152:4039-45
Vandanmagsar, Bolormaa; Youm, Yun-Hee; Ravussin, Anthony et al. (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179-88