Over two-thirds of the population in the United States and globally are over-weight or obese. The increased risk of chronic diseases among obese, including cardiovascular, respiratory diseases and cancer is well established. However, it was recognized only recently that obesity also increases risk for infectious disease morbidity and mortality. The growing obesity epidemic suggests a large proportion of the population is at risk, but the mechanisms explaining the increased risk of infection among obese are largely unknown. Given the high prevalence of obesity in the population, understanding how molecular and cellular responses vary among obese vs. non-obese can provide important insights into reducing risk and treatment among this susceptible population. Toll-like receptors (TLRs), responsible for pathogen detection, may provide important clues in understanding the relationship between obesity, immune function and the environment. TLRs play a key role in orchestrating the immune response to infections by detecting diverse pathogen-associated molecules from viruses, bacteria, fungi or protozoa and producing cytokines and other inflammatory mediators. Interestingly, recent studies have also revealed that TLR2 and TLR4 mediate immune responses to air pollutants as particulate matter can carry microbes that activate TLRs and trigger inflammatory responses. TLR4 is most studied TLR, but very little is known about the entire spectrum of other TLRs and the role they play in obesity. Furthermore, there are no population-based studies to date systemically examining the effects of obesity on the expression and function of TLRs. We hypothesize that obesity suppresses TLR expression and/or function leading to abnormal responses to pathogens and exogenous agents. We will test our hypothesis using human peripheral blood mononuclear cells (PBMCs) available through the Survey of the Health of Wisconsin, a well-established ongoing annual population-based health survey. PBMCs will be analyzed for TLR1-TLR10 expression (Aim 1). In addition, TLRs inflammatory responses will be analyzed in freshly prepared PBMCs that will be stimulated ex vivo with TLR ligands (Aim 2). To date, no human studies have examined the breadth of TLRs response in obesity. Therefore, the goals of this high-risk/high-reward research are to investigate how obesity alters expression and function of TLRs, and will provide important insight into the mechanisms by which obesity alters human response to pathogens and environmental exposures, and the role of TLRs in driving human sensitivity and response.

Public Health Relevance

It is well known that obesity increases the risk for heart diseases, diabetes and cancer. It was recognized only recently that obese individuals are also at higher risk for infectious diseases, like flu or pneumonia, and complications arising from them. In this study, we will investigate how obesity affects Toll-like receptors (TLRs) in the immune system. TLRs detect viruses, bacteria or fungi and initiate body response with a goal to eliminate these pathogens. This research will advance our understanding on how obesity makes people more sensitive to their environment and more vulnerable to infections. It will help inform new prevention and treatment strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Vazquez-Maldonado, Nancy
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University of Wisconsin Madison
Public Health & Prev Medicine
Schools of Medicine
United States
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