IMMUNE MODULATION OF METABOLISM: THE ROLE OF MACROPHAGES, NKT\ud CELLS AND DENDRITIC CELLS IN THE DEVELOPMENT OF THE METABOLIC\ud DISTURBANCES OF OBESITY

It is now established that adipose tissue macrophages, which accumulate in obese individuals and rodents, play a key role in the generation of a low-grade, chronic inflammation, as well as the development of steatosis and insulin resistance, when faced with chronic overnutrition. The hypothesis of this dissertation is that other cells of the immune system and inflammatory responses within other insulin sensitive organs are also involved in the metabolic regulation of nutrient utilization. Specifically, we tested the responses of dendritic cells (DC), Kupffer cells (KC, the resident macrophages of the liver) and Natural Killer T (NKT) cells in the liver, as well as in adipose tissue. \ud To address this hypothesis, we developed two model systems to artificially alter the immune system while monitoring changes within the liver and/or adipose tissue. First, we established an in vitro co-culture model of the liver with mouse hepatocytes and KC to study interactions between the two cell types. Second, we established an adoptive transfer protocol to exogenously increase the numbers of macrophages and various types of DC in mice consuming a high fat diet. Finally, we utilized the CD1d-/- mouse line to clarify an important controversy regarding the involvement of NKT cells in the metabolic disturbances of obesity.\ud We found that KC decrease hepatocyte palmitate oxidation and identified prostaglandin E2 (PGE2) as a potential mediator of this effect. Furthermore, the liver and adipose tissue of mice receiving weekly injections of immature bone marrow-derived DC are skewed towards a predominantly TH2, or anti-inflammatory, phenotype. Additionally, these mice accumulate less fat and are partially protected against diet-induced insulin resistance. Also, we illustrate that removal of NKT cells does not alter insulin resistance or steatosis when consuming a high fat diet (HFD).\ud In conclusion, we have demonstrated that responses of immune cells within the\ud liver alter lipid metabolism and can induce changes consistent with the development of steatosis. Additionally, DC play an integral role in the determination of body composition and insulin sensitivity when challenged with a HFD. And finally, NKT cells may not be involved in the development of the metabolic disturbances of obesity