The Effects of Obesity, Weight Loss, and Weight Cycling on the Immunometabolic Properties of Mouse Adipose Tissue

Abstract

Obesity is a prevalent disorder that increases the risk of developing many metabolic diseases, including insulin resistance (IR) and type 2 diabetes. Research conducted in the past decade has shown that accumulation of immune cells in obese adipose tissue (AT) contributes to inflammation and IR both locally and systemically. As a result of these novel findings, the immune system has come to the forefront of obesity research. However, many questions remain in this emerging field of immunometabolism. The studies in this dissertation have contributed to the understanding of: 1) the factors within the local milieu of obese AT that influence the phenotype and activation status of AT macrophages (ATMs), 2) the mechanisms regulating macrophage accumulation in AT during obesity and weight loss, and 3) the role of adaptive immune cells in the AT during weight cycling. First, I have shown in vitro that free fatty acid accumulation in macrophages activates inflammatory signaling, leading to endoplasmic reticulum (ER) stress-mediated apoptosis. However, pharmacological activation of lipolysis in obese AT does not result in ATM lipotoxicity. Second, I have demonstrated that ATM apoptosis occurs in lean AT, is decreased during obesity, and is “re-activated” after weight loss. These findings suggest that ATM apoptosis is a novel mechanism by which ATM number is maintained. Interestingly, ATM ER stress signaling was regulated in a similar manner, but did not play a role in the activation of macrophage apoptosis. Third, I have shown that weight cycling increases the accumulation of pro-inflammatory T cell subsets in AT, suggesting that a nutritionally regulated local secondary adaptive immune response may occur. Overall, the studies in this dissertation have made important contributions to the field of immunometabolism by increasing our understanding of the dynamic regulation of AT immune cell composition and activation status in various nutritional states including obesity, weight loss, and weight cycling.