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Peroxisome proliferator-activated receptor γ(PPARγ, NR1C3) and testicular receptor 4 nuclear receptor (TR4, NR2C2) are two members of the nuclear receptor (NR) superfamily that can be activated by several similar ligands/activators including polyunsaturated fatty acid metabolites, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, as well as some anti-diabetic drugs such as thiazolidinediones (TZDs). However, the consequences of the transactivation of these ligands/activators via these two NRs are different, with at least three distinct phenotypes. First, activation of PPARγ increases insulin sensitivity yet activation of TR4 decreases insulin sensitivity. Second, PPARγ attenuates atherosclerosis but TR4 might increase the risk of atherosclerosis. Third, PPARγ suppresses prostate cancer (PCa) development and TR4 suppresses prostate carcinogenesis yet promotes PCa metastasis. Importantly, the deregulation of either PPARγ or TR4 in PCa alone might then alter the other receptor's influences on PCa progression. Knocking out PPARγ altered the ability of TR4 to promote prostate carcinogenesis and knocking down TR4 also resulted in TZD treatment promoting PCa development, indicating that both PPARγ and TR4 might coordinate with each other to regulate PCa initiation, and the loss of either one of them might switch the other one from a tumor suppressor to a tumor promoter. These results indicate that further and detailed studies of both receptors at the same time in the same cells/organs may help us to better dissect their distinct physiological roles and develop better drug(s) with fewer side effects to battle PPARγ- and TR4-related diseases including tumor and cardiovascular diseases as well as metabolic disorders. [ABSTRACT FROM AUTHOR]