The role of fat cell apoptosis during obesity-associated adipose tissue inflammation

Abstract

Obesity-associated macrophage infiltration into adipose tissue is responsible for both local and systemic inflammation. The initial event, however, that triggers macrophage infiltration, has yet to be identified. We hypothesize that apoptosis is involved in the inflammatory process of adipose tissue and persued an in vivo as well as an in vitro approach to elucidate a possible connection of fat cell apoptosis and macrophage accumulation in the human adipose tissue. For the in vivo study we subjected serial sections of human subcutaneous and visceral adipose tissue immunohistochemical analysis. We localized CD11c+-macrophages around apoptotic adipocytes in both fat depots. Additionally, the percentage of apoptotic adipocytes strongly correlated with the percentage of macrophages (sc: r = 0.888; p < 0.001; visc: r = 0.560, p = 0.003), supporting the idea of a connection between macrophage infiltration and fat cell apoptosis. To investigate the effects of an inflammatory micro-environment on fat cells, we established a human in vitro model system of inflamed adipose tissue by using THP-1 macrophages and SGBS adipocytes. Macrophage-secreted factors (MacCM) induced insulin resistance and inhibited insulin-stimulated Akt phosphorylation in adipocytes. Furthermore, macrophage-secreted factors induced apoptosis of fat cells. This apoptosis-inducing effect was even more pronounced in direct co-cultures of adipocytes and macrophages. Our data suggest a link between insulin resistance and apoptosis sensitivity. Accordingly, pharmacological and genetic inhibition of insulin signaling at the level of Akt2 sensitized adipocytes to apoptosis induction by macrophage-secreted factors. In conclusion, we describe here a novel interaction of macrophages and fat cells, i.e. induction of apoptosis. Our data suggest a feed-forward cycle in which macrophages further drive the inflammatory process by inducing insulin resistance and concomitant apoptosis of adipocytes.