Turnover of Adipose Tissue Macrophages

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DESCRIPTION (provided by applicant): The progressive recruitment of macrophages to adipose tissue (AT) is a hallmark of diet-induced obesity and is thought to be key for the development of insulin resistance both in AT and peripheral tissues. Because of the importance of AT macrophage (ATM) accumulation most investigators in the field have focused almost exclusively on the molecular mechanisms mediating their recruitment. However, AT is one of the most plastic tissues in the body, with the capacity to expand and contract dramatically during positive and negative energy balance. It was therefore reasoned that ATM accumulation is likely to be a dynamic event reflecting a balance of ATM recruitment, retention, and removal. This led to the consideration that the accelerated accumulation of macrophages in AT during its expansion might in fact primarily reflect a defect in ATM removal rather than simply reflecting increased recruitment. In this application exciting new preliminary data is presented showing that ATM cell death may be an important physiological mechanism mediating ATM turnover and contributing to AT homeostasis during weight loss. First, Western blot analysis shows that apoptosis markers are lower in macrophage-enriched SVFs of AT from obese compared to lean mice. Second, immunofluorescence staining demonstrates decreased TUNELpos;F4/80pos (apoptotic macrophages) in obese compared to lean AT. The higher levels of apoptosis in lean ATMs suggest that ATM cell death may be a physiologically regulated process in lean AT that becomes impaired during obesity. In support of the concept that ATM turnover is regulated, our data demonstrate that ATM apoptosis is "restored" during weight loss. These novel observations have led us to consider the possibility that apoptosis is essential to ATM turnover and removal to maintain healthy AT. Thus, the hypothesis to be tested in this application is: apoptosis contributes to the homeostatic maintenance of macrophage numbers in AT. Implicit within this hypothesis is that a decrease in ATM turnover during weight gain occurs in parallel with increased recruitment of new macrophages and may contribute to the retention of macrophages within AT during obesity. This hypothesis is striking in that it focuses on recruitment-independent mechanisms for ATM accrual in obesity. Our studies will address a critical void in the current understanding of mechanisms by which the immune system responds to the metabolic stresses incurred during weight gain and loss. Our hypothesis will be tested in the following aims: Specific Aim 1: To determine the temporal and spatial regulation of ATM apoptosis. We hypothesize that ATM apoptosis is impaired during positive energy balance and restored during negative energy balance. Specific Aim 2: To determine whether eosinophils regulate ATM apoptosis. We hypothesize that eosinophils regulate the apoptosis and turnover of ATMs. Specific Aim 3: To determine the physiological consequences of impaired ATM apoptosis. We hypothesize that inhibition of macrophage apoptosis will result in increased ATM content as well as local and systemic IR.