The peroxisome proliferator-activated receptor y (PPAR) regulates adipocyte differentiation and glucosehomeostasis and is the molecular target of thiazolidinediones that act as insulin-sensitizers in patients withtype 2 diabetes. PPAR? is also expressed in macrophages and negatively regulates the program ofmacrophage activation by repressing a subset of AP-i and NK-KB-dependent genes. The recent discoverythat macrophages accumulate in obese adipose tissue and are a major source of inflammatory mediators thatare linked to insulin resistance raises the possibility that the macrophage is a key target of the anti-diabeticactions of TZDs. Consistent with this, selective deletion of the PPAR? gene from macrophages results in mildinsulin resistance in lean animals and a more severe degree of insulin resistance in diet-induced obesity.Studies performed in collaboration with the Rosenfeld laboratory have uncovered a mechanistic pathway bywhich PPAR? inhibits inflammatory gene expression in activated macrophages that involves the nuclearreceptor co-repressor, N-CoR. This Project will test the overall hypothesis that adipocyte-macrophageinteractions drive inflammatory programs of gene expression that contribute to insulin resistance and thatTZDs act as insulin sensitizers in part by counter-regulating these responses in macrophages.
Four SpecificAims are proposed:
Specific Aim i will define PPAR? and N-CoR-dependent gene networks in macrophagesusing a combination of gene expression profiling and ChlP-Chip technologies. These studies will test thehypothesis that N-CoR co-repressor complexes are required for PPAR?-mediated repression of broad sets ofinflammatory response genes and will complement studies in Project 2 examining glucose homeostasis inmice reconstituted with N-CoR-deficient macrophages.
Specific Aim 2 will investigate the basis for insulinresistancein mice selectively lacking PPAR? expression in macrophages. In collaboration with Project i,these studies will evaluate macrophage accumulation and gene expression in adipose tissue, skeletal muscleand livers of wild type mice and mice lacking PPAR? expression in macrophages.
Specific Aim 3 will test thehypothesis that PPAR? counter-regulates pro-inflammatory programs of gene expression induced by freefatty acids. This will be accomplished by determining the effects of free fatty acids on macrophage geneexpression in control and PPAR?-deficient macrophages and by evaluating the ability of free fatty acids tostimulate the transrepression activities of PPAR?.
Specific Aim 4 will utilize selective modulators of PPAR? totest the hypothesis that insulin-sensitizing activities of PPAR? can be achieved through either activation ofdirect target genes in adipocytes or through transrepression of inflammatory response genes in macrophages.These studies have implications for novel approaches to treatment of obesity-induced diabetes.
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