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(-/-) 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(-/-) 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.
Kawai
Masanobu
M
The Musculoskeletal Laboratory, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Green
Carla B
CB
Lecka-Czernik
Beata
B
Douris
Nicholas
N
Gilbert
Misty R
MR
Kojima
Shihoko
S
Ackert-Bicknell
Cheryl
C
Garg
Neha
N
Horowitz
Mark C
MC
Adamo
Martin L
ML
Clemmons
David R
DR
Rosen
Clifford J
CJ
D021581:Active Transport, Cell Nucleus; D050156:Adipogenesis; D000818:Animals; D001823:Body Composition; D002460:Cell Line; D019070:Cell Lineage; D002940:Circadian Rhythm; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
D009687:Nuclear Proteins; D047495:PPAR gamma; D014157:Transcription Factors; C102804:nocturnin