Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcriptional factors. Among other functions, PPAR-gamma acts as a key regulator of the adipogenesis. Since several cytokines (IL-1, TNF-alpha, TGF-beta) had been known to inhibit adipocyte differentiation in mesenchymal stem cells (MSCs), we examined the effect of these cytokines on the transactivation function of PPAR-gamma. We found that the TNF-alpha/IL-1-activated TAK1/TAB1/NIK (NFkappaB-inducible kinase) signaling cascade inhibited both the adipogenesis and Tro-induced transactivation by PPAR-gamma by blocking the receptor binding to the cognate DNA response elements. Furthermore, it has been shown that the noncanonical Wnts are expressed in MSCs and that Wnt-5a was capable to inhibit transactivation by PPAR-gamma. Treatment with Wnt5a-activated NLK (nemo-like kinase) induced physical association of the endogenous NLK and H3K9 histone methyltransferase (SETDB1) protein complexes with PPAR-gamma. This resulted in histoneH3K9 tri-methylation at PPAR-gamma target gene promoters. Overall, our data show that cytokines and noncanonical Wnts play a crucial role in modulation of PPAR-gamma regulatory function in its target cells and tissues.