NOCing PPAR-γ into the Nucleus?

Science Signaling  15 Jun 2010:
Vol. 3, Issue 126, pp. ec180
DOI: 10.1126/scisignal.3126ec180

Various genes involved in metabolism show circadian variations in expression, and alterations in circadian time-keeping may increase the risk for development of metabolic syndrome and obesity. Activity of the transcription factor peroxisome proliferator–activated receptor γ2 (PPAR-γ2, which is expressed rhythmically) has been implicated in bone marrow osteogenesis versus adipogenesis. Noting that mice lacking Nocturnin (NOC, a deadenylase that is also expressed rhythmically) are resistant to diet-induced obesity and fail to show rhythmicity in the expression of Pparg2, the gene encoding PPAR-γ2, Kawai et al. explored interactions between NOC and PPAR-γ2 that might facilitate adipogenesis. Noc mRNA abundance was increased in 3T3-L1 cells exposed to adipogenic factors, and an increase in NOC abundance was apparent early in adipogenesis. Noc overexpression in 3T3-L1 cells promoted adipogenesis and increased the expression of adipogenic markers (including Pparg2), whereas its knockdown decreased adipogenesis and the expression of adipogenic markers. In contrast, Noc expression was decreased in primary calvarial osteoblasts treated with osteogenic factors; its overexpression inhibited osteoblastogenesis in MC3T3-E1 cells, whereas its knockdown stimulated osteoblastogenesis. NOC coimmunoprecipitated with PPAR-γ2, and, although it failed to increase basal transcription of a reporter containing a Pparg response element, it enhanced its activation in the presence of the PPAR-γ agonist rosiglitazone. Mutational analysis indicated that the ability of NOC to immunoprecipitate with and enhance PPAR-γ2 transcriptional activity was independent of its deadenylase activity. Immunofluorescence analysis revealed that NOC had a perinuclear distribution, and immunofluorescence analysis, together with cell fractionation combined with Western analysis, indicated that NOC facilitated PPAR-γ2 nuclear translocation, an effect that involved a NOC region (amino acids 341 to 351) with a sequence resembling a Src homology 2 domain binding motif. Phenotypic analysis of the Noc–/– mice resistant to obesity showed fewer bone marrow adipocytes than in control mice, a decrease in brown adipose tissue Pparg2 expression and ex vivo function, and an increase in bone mineral density. The authors propose that NOC, which is related to yeast transcription factors implicated in the response to nutrient status, promotes the nuclear translocation of PPAR-γ2 and thereby adipogenesis.

M. Kawai, C. B. Green, B. Lecka-Czernik, N. Douris, M. R. Gilbert, S. Kojima, C. Ackert-Bicknell, N. Garg, M. C. Horowitz, M. L. Adamo, D. R. Clemmons, C. J. Rosen, A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-γ nuclear translocation. Proc. Natl. Acad. Sci. U.S.A. 107, 10508–10513 (2010). [Abstract] [Full Text]