On a daily basis, we turnover billions of apoptotic cells that are removed by phagocytic cells, such as macrophages. The processes of cell death and phagocytic clearance are vital to maintaining homeostasis and are related to many disease pathologies. The adipose tissue has been reported to undergo basal turnover, and during conditions of obesity, apoptotic adipocytes have been shown to increase in mice and humans. This cell death and subsequent macrophage infiltration to clear the dying cells has been described as a key inducer of inflammation and causative in the development of insulin resistance. This inflammation has been specifically attributed to macrophage activity, as depletion of macrophages reduces inflammation and improves insulin sensitivity. Interestingly, these macrophage depletion conditions do not result in the accumulation of dead cells, possibly demonstrating additional phagocytic population(s). In addition to professional phagocytes (such as macrophages), non-professional phagocytes also exist, such as epithelial cells in the digestive tract and lung, or mesenchymal cells during embryonic limb development. These non-professional phagocytes can play vital roles in maintaining homeostasis, yet in the adipose tissue no such population has been defined thus far. Based on preliminary studies, we propose to investigate specific non-professional phagocytic cell populations in the adipose tissue and define how these cells contribute to inflammation, inflammation resolution, and insulin resistance associated with obesity. PtdSer is a lipid specifically exposed on the surface of apoptotic cells and is used by phagocytic cells for clearance. To allows us to better manipulate the phagocytic activity of these cell populations, we will additionally investigate the role of phosphatidylserine (PtdSer) receptors. Understanding cell types, the phagocytic process, and molecular players during homeostasis and adipose tissue inflammation will provide important therapeutic opportunities for obesity.
Diabetes affects 25 million individuals in the United States, and 90% of these cases are type 2 diabetes resulting from obesity. Cell death is a key process in type 2 diabetes pathology and the clearance of these dying cells by the cells of the immune system seems to promote harmful inflammation leading to insulin resistance. This proposal aims to study the process of dead cell clearance in obesity, specifically identifying and characterizing the previously unappreciated cell types as well as the specific molecules involved, with the goal of manipulation of these cells and molecules for obesity and type 2 diabetes therapies.
