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The role of p16INK4a in the development of obesity and insulin resistance (P16 and metabolism)
Start date: 02 Mar 2009, End date: 01 Mar 2011 PROJECT  FINISHED 

Genome-wide association studies have linked the CDKN2A locus to an increased risk of Type 2 Diabetes (T2D), which is mostly accompanied by insulin resistance (IR) and obesity. The CDKN2A locus encodes p16INK4a, a tumor suppressor. p16INK4a is an inhibitor of cyclin-dependent kinases, which regulate the cell cycle. Recent studies have shown a link between p16INK4a and the control of inflammation. T2D is an inflammatory disease, in which macrophages are important effector cells. Moreover, adipose tissue macrophages (ATMs) have been found necessary and sufficient for IR to develop. Resident ATMs are known to display an anti-inflammatory “M2” phenotype. Upon obesity, a switch towards a pro-inflammatory “M1” phenotype has been described, inducing adipocyte dysfunction and systemic IR. Additionally, recent findings from the host laboratory indicate that macrophages lacking p16INK4a exhibit a M2 phenotype. Therefore, we hypothesize that p16INK4a may play a role in the development of IR and obesity, possibly by influencing macrophage polarization. To study the role of macrophage p16INK4a in obesity and IR, we will perform a series of bone marrow transplantation experiments, creating mice that lack p16INK4a immune cells (like ATMs) but not in other cells of the body. Several metabolic parameters, like insulin and glucose tolerance, will be analyzed in vivo. Tissues of these animals will be examined thoroughly on mRNA and protein level. The molecular mechanisms of p16INK4a action on macrophage polarization will be further investigated with microarray analysis of isolated ATMs. In addition, the effects of p16INK4a deficient macrophages on adipocytes will be determined in vitro via direct and indirect co-culture experiments. Finally, using this experimental setup of co-culture, the influence of peroxisome proliferator activated receptors on the interplay between ATMs and adipocytes will be determined.
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