There is a growing world-wide obesity epidemic that is linked to hyperlipidemia, inflammation, and insulin resistance. The presence of obesity and these down-stream metabolic effects greatly increases the risk of development of diabetes and cardiovascular disease. There are many different factors leading to increased adiposity, with the quantity and composition of dietary fats contributing heavily to this epidemic. Consumption of saturated fatty acids (SFAs) has been shown to be associated with increased risk of atherosclerotic disease as well as IR, while diets rich in polyunsaturated fatty acids (PUFAs) are protective against these conditions. Macrophages, cells of the innate immune system, have been demonstrated to infiltrate white adipose tissue (WAT) in obese rodents and humans. Increased macrophages accumulation in WAT is associated with local and systemic inflammation, and their accumulation has also been shown to temporally precede the development of IR. Thus, adipose tissue macrophages (ATMs) are key mediators of the pathophysiological consequences of obesity. Our preliminary data are consistent with the idea that not only obesity, but also dietary fatty acid composition, can influence macrophage infiltration into WAT, local and systemic inflammation, and IR. Our data are also in support of a role for Toll-like receptor 4 (TLR4) in SFA- induced monocyte migration. Consequently, the overall working hypothesis of this proposal is: SFAs can initiate macrophage recruitment to WAT by both chemokine-dependent and -independent mechanisms and that macrophaqe TLR4 expression mediates this SFA-responsive migration. A corollary to this hypothesis is that PUFAs can blunt SFA-induced macrophage migration. This hypothesis will be tested in three specific aims: (1) To determine whether dietary SFAs promote macrophage infiltration of WAT via increasing adipocyte or ATM chemokine expression, (2) To determine whether SFAs can promote macrophage migration independently of chemokine expression, and (3) To distinguish between TLR4-dependent and -independent processes effecting monocyte recruitment to WAT. We will utilize in vitro methods to determine whether SFAs can act as chemoattractants and whether exposure of monocytes to SFAs increases their migratory potential. In addition, we will use obesity-prone mice to study, in vivo, the effects of dietary fatty acids, fatty acid mobilization in WAT, and macrophage TLR4 expression on ATM accumulation. The clinical consequences of obesity, including diabetes and cardiovascular disease are placing a tremendous burden on our health care system. A better knowledge of mechanisms by which macrophages sense and respond to dietary fatty acids, leading to their recruitment and activation in WAT is imperative for our understanding of their contribution to obesity-related syndromes. ? ? ?
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