A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-[gamma] nuclear translocation

Nocturnin (NOC) is a circadian-regulated protein related to the yeast family of transcription factors involved in the cellular response to nutrient status. In mammals, NOC functions as a deadenylase but lacks a transcriptional activation domain. It is highly expressed in bone-marrow stromal cells (BMSCs), hepatocytes, and adipocytes. In BMSCs exposed to the PPAR-[gamma] (peroxisome proliferator-activated receptor-[gamma]) agonist rosiglitazone, Noc expression was enhanced 30-fold. Previously, we reported that [Noc.sup.-/-] mice had low body temperature, were protected from diet-induced obesity, and most importantly exhibited absence of Pparg circadian rhythmicity on a high-fat diet. Consistent with its role in influencing BMSCs allocation, [Noc.sup.-/-] mice have reduced bone marrow adiposity and high bone mass. In that same vein, NOC overexpression enhances adipogenesis in 3T3-L1 cells but negatively regulates osteogenesis in MC3T3-E1 cells. NOC and a mutated form, which lacks deadenylase activity, bind to PPAR-[gamma] and markedly enhance PPAR-[gamma] transcriptional activity. Both WT and mutant NOC facilitate nuclear translocation of PPAR-[gamma]. Importantly, NOC-mediated nuclear translocation of PPAR-[gamma] is blocked by a short peptide fragment of NOC that inhibits its physical interaction with PPAR-[gamma]. The inhibitory effect of this NOC-peptide was partially reversed by rosiglitazone, suggesting that effect of NOC on PPAR-[gamma] nuclear translocation may be independent of ligand-mediated PPAR-[gamma] activation. In sum, Noc plays a unique role in the regulation of mesenchymal stem-cell lineage allocation by modulating PPAR-[gamma] activity through nuclear translocation. These data illustrate a unique mechanism whereby a nutrient-responsive gene influences BMSCs differentiation, adipogenesis, and ultimately body composition. doi/ 10.1073/pnas.1000788107