The obesity-induced macrophage: a new player in at.. (MacObesity)
The obesity-induced macrophage: a new player in atherosclerosis development
Start date: Sep 1, 2012,
End date: Aug 31, 2016
Obesity is an independent risk factor for atherosclerosis but the exact mechanistic link between these conditions is unknown. Parallel to atherogenesis, obesity induces the recruitment of pro-inflammatory macrophages from bone marrow to adipose tissue (AT).We hypothesize that obesity-induced macrophages, through interactions with adipose tissue-derived free fatty acids, are important players in atherosclerosis development and thereby represent the key link between these conditions.First, we will investigate the effects of obese AT on the phenotype and function of adipose tissue macrophages (ATMs) and the consequences for atherogenesis. Since it is known that obesity leads to recruitment of CD11c-positive, dendritic cell-like ATMs, the effects of local AT-derived free fatty acids (FFAs) on ATM phenotype and their antigen-presenting capacity will be assessed in vitro and in vivo using mouse models. Additionally, we will isolate CD11c-positive and CD11c-negative (resident) ATMs from obese AT and compare them by genome-wide expression analysis and functional studies. Moreover, the effects of ATMs on adaptive immune responses and atherosclerosis will be assessed by transplantation of obese AT to atherosclerosis-prone low-density lipoprotein receptor deficient (ldlr-/-) mice. Second, we will investigate the effects of FFAs on the differentiation of macrophages from bone marrow cells and the consequences for atherosclerosis development. Hereto, we will determine how FFAs affect differentiation of bone marrow cells into macrophages by performing functional characterization. The obtained results will be evaluated in vivo by adoptive transfer of bone marrow-derived macrophages, treated ex vivo with FFAs during their differentiation, to ldlr-/- mice. Atherosclerosis development and alterations in the immune response will be measured in detail. Finally, we will validate the results in human patient material identifying novel diagnostic markers and therapeutic targets.
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