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Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear hormone receptor involved in maintaining glucose and fatty acid homeostasis. Besides its metabolic functions, the receptor has also been implicated in tumorigenesis. Ligands of PPAR gamma induce apoptosis in several types of tumor cells including lymphomas, leading to the proposal that these ligands may be used as anti-cancer agents. However, apoptosis induction requires high doses of ligands, suggesting the effect may not be receptor-dependent. Previously, we reported that PPAR gamma is expressed in human primary T cell lymphoma tissues and activation of PPAR gamma with low doses of ligands protects lymphoma cells from serum starvation-induced apoptosis. The prosurvival effect of PPAR gamma is linked to its actions on mitochondria. In serum-deprived cells, PPAR gamma attenuates the decline in ATP, reduces mitochondrial hyperpolarization and limits the amount of reactive oxygen species (ROS) in favor of cell survival (Yang et al, Am J Pathol, 170, 722–32, 2007). In the current study, we investigated the molecular mechanisms by which PPAR gamma maintains mitochondria homeostasis. We demonstrated that PPAR gamma modulates the activities of two key components of Wnt signaling pathway, Fzd4 and GSK-3 beta. The receptor up-regulates the mRNA expression of Fzd4, a cell surface receptor of Wnt, through a conserved PPAR-response element (PPRE) in the promoter region of the Fzd4 gene. Moreover, PPAR gamma suppresses the activation of GSK-3 beta, a downstream inhibitory serine/threonine kinase, by maintaining its phosphorylation at serine 9 and decreasing its association with mitochondria. Downregulation of GSK-3 beta activity results in maintenance of mitochondrial membrance potential and suppression of ROS production in growth factor-deprived cells. Our studies revealed a novel interaction between PPAR gamma and Wnt signaling in lymphocyte survival. Since Wnt signaling plays an important role in tumorigenesis, our studies highlight the need for further investigation into the role of PPAR gamma in cancer prior to widespread use of its agonists as anticancer therapeutics.