Dietary Exposures Contribute to Different Diseases through the Microenvironment Public Deposited

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  • March 19, 2019
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  • Qin, Yuanyuan
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
Abstract
  • Genetic predispositions play an important role in our health, but these are not absolute; lifestyle choices help determine how long and how well we live. The global pandemic of obesity and related diseases is a good example. Lifestyle can contribute to diseases through altering the microenvironment of important tissues including adipose in obesity. In this dissertation, the consequences of lifestyle components on local and systemic inflammation and hyperinsulinemia were investigated, both of which contribute to risk of diseases such as obesity, insulin resistance, and breast cancer. Using preclinical mouse models, we aimed to uncover mechanisms by which alcohol and obesogenic diet exposures alter the microenvironment in the pathogenesis of adipose and mammary gland dysfunction. We found that binge ethanol exposure followed by burn injury exacerbated the adipose inflammatory response induced by burn alone, with significant elevations in macrophage infiltration and secretion of pro-inflammatory mediators when compared to controls not exposed to binge alcohol intake. It is well established that adipose inflammation contributes to insulin resistance, especially associated with obesity. We discovered that fatty acid transporter 1 (FATP1) predominantly on alternatively activated macrophages contributes to decreased local and systemic inflammation. Macrophage FATP1 overexpression suppressed inflammatory response, while FATP1 knock out exaggerated inflammatory factor expression in vitro. Mice transplanted with Fatp1-/- bone marrow and fed an obesogenic diet gained more weight and greater epididymal white adipose accretion, and became hyperglycemic and glucose intolerant. Obesity is a strong risk factor for an aggressive subtype of breast cancer called basal-like breast cancer (BBC) and reducing adiposity is predicted to lower incidence of BBC in human populations. Thus, we made mice obese in early adulthood and induced weight loss by a diet intervention. Mice, which lost weight following an initial weight gain, reversed obesity-driven tumor aggressiveness and mammary gland hyperplasia and ductal carcinoma in situ through alterations in kinase activation. The obese microenvironment of mammary glands in adulthood therefore can promote early tumor onset. Importantly the composition of the mammary gland can be reprogrammed with weight loss and restored to a lean phenotype associated with significantly reduced tumor aggressiveness.
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  • In Copyright
Advisor
  • Zeisel, Steven H.
  • Makowski, Liza
  • Troester, Melissa
  • Perou, Charles
  • Beck, Melinda A.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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