Suppression of colon carcinogenesis by peroxisome proliferator-activated receptor-gamma (PPAR) is likely due to some effect of PPAR on normal colonic epithelial cells. However, our understanding of the effects of PPAR in such cells is limited. We have analyzed the abundance, distribution, and function of PPAR in epithelial cells isolated form the murine proximal and distal colon. Marked differences in PPAR abundance and distribution were observed, suggesting tissue-specific responses. Analysis of PPAR effects on DNA synthesis, formation of pre-neoplastic lesions, and activation of MAPK signaling in proximal and distal colonic epithelial cells in vivo indicates that PPAR regulates both tssue-specific and common responses within the proximal and distal colon. Three major functional cohorts of PPAR target genes were identify by genomic profiling of isolated colonic epithelial cells: genes that are involved in metabolism, in signaling, and in cellular adhesion and motility. Two subsets of PPAR target genes were differentially expressed in the proximal and distal epithelial. Proximal target genes were primarily involved in metabolic activities, whereas signal transduction, adhesion, and motility targets were more pronounced in the distal colon. Remarkably, those target genes that are differentially expressed in the proximal colon were all induced upon activation of PPAR, whereas all target genes that are preferentially expressed in the distal colon were repressed. Our data indicate that PPAR exerts both common and tissue-specific effects in the colon and challenge the general conclusions that PPAR is induced upon differentiation of colonic epithelial cells and that this receptor stimulates differentiated function throughout the colon.