Investigating the Role of Interleukin-15 in Modulating Adipose Tissue

Abstract

<p>Obesity is a major global health concern and is associated with the development of numerous non-communicable diseases. A thorough understanding of the onset of obesity is critical to the development of effective therapeutic strategies against this disease state. Recently, obesity has been described as a complex disease characterized by chronic low grade inflammation. Abnormal adipose tissue expansion is accompanied by an increased presence of proinflammatory immune cells, dysregulated adipokine expression, oxidative stress, and is associated with significant changes in the bacterial composition of the gut. While interleukin-15 (IL-15) has been studied extensively for its immunological effects, this cytokine has recently been shown to influence body weight and fat mass. The focus of this thesis was to elucidate the role of and mechanism by which IL-15 modulates adipose tissue. Our first study demonstrated that low levels of IL-15 expression are associated with adiposity and promotes an obese state in IL-15-/- mice and human subjects, while IL-15 overexpression was associated with a lean phenotype in IL-15tg mice when compared to appropriate controls. To uncover the underlining mechanisms by which IL- 15 mediates differences in body weight, we subsequently determined that IL-15 mediated weight loss occurred independently of lymphocytes. In another study, we showed that IL-15tg mice had increased mitochondrial activity and mass specific to adipose tissue compared to IL-15-/- and B6 mice, while acute IL-15 administration induced the expression of FAO markers in adipose tissue. Lastly, IL-15 treatment increased mitochondrial membrane potential and decreased lipid deposition in cultured adipocytes, suggesting that IL-15 may mediate its effects directly on adipose tissue. The experimental results presented in this thesis demonstrate that IL-15 is an important regulator of adipose tissue and body weight. Future studies examining the effects of IL- 15 on adipose tissue will further our knowledge on IL-15 biology, and may contribute to novel therapeutic strategies for the treatment and prevention of obesity.</p>