Preadipocyte IL-13-IL-13Rα1 signaling regulates beige adipogenesis through modulation of PPARɣ activity

Abstract

Obesity is a complex metabolic disorder that poses significant challenges to public health and individual wellbeing. While diet and exercise serve as valuable first line treatments for obesity, additional approaches are needed to enhance weight loss and mitigate the metabolic consequences of excess adiposity, including type 2 diabetes. Thermogenic beige adipocytes are a promising target for the development of new metabolic therapies; upon activation by environmental cold and adrenergic stimuli, these cells take up glucose and fatty acids to fuel uncoupled respiration, thereby expending energy and producing heat. Designing therapies that harness the benefits of beige adipocytes requires knowledge of the factors that govern their development and function, such as the innate immune system. In this dissertation, I will discuss how interleukin 13 (IL-13) signaling via interleukin 13 receptor subunit alpha 1 (IL-13Rα1) regulates beige adipogenesis to promote glucose homeostasis and the maintenance of a healthy body weight. In the first study, I demonstrate that preadipocyte IL-13/IL-13Rα1 signaling promotes thermogenesis and the de novo recruitment of beige adipocytes in post-natal development. IL-13 increases the expression and activity of peroxisome proliferator-activated receptor gamma (PPARɣ) to induce the transcription of oxidative and thermogenic genes, an effect mediated, in part, by enhanced coactivation of PPARɣ by peroxisome proliferator- activated receptor gamma coactivator 1 alpha (PGC-1α). I also discuss an additional role for IL- 13/IL-13Rα1 in regulating the activity of the β3 adrenergic signaling axis in mature beige adipocytes, thereby enhancing their thermogenic and lipolytic potential. In the second study, I utilize an in vitro approach to propose additional pathways by which preadipocyte IL-13/IL-13Rα1 signaling may promote beige adipogenesis, including the retinoic acid and prostaglandin synthesis pathways. Finally, I propose a role for IL-13 in suppressing the fibrotic smooth muscle developmental program in bipotential preadipocytes. Collectively, my dissertation establishes the IL-13/IL-13Rα1/PPARɣ signaling axis as a dynamic mediator of beige adipocyte development and metabolic homeostasis.