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PNAS 107 (23): 10508-10513

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

A circadian-regulated gene, Nocturnin, promotes adipogenesis by stimulating PPAR-{gamma} nuclear translocation

Masanobu Kawaia, Carla B. Greenb,1, Beata Lecka-Czernikc, Nicholas Dourisb, Misty R. Gilbertb, Shihoko Kojimab,1, Cheryl Ackert-Bicknelld, Neha Garge, Mark C. Horowitzf, Martin L. Adamoe, David R. Clemmonsg, and Clifford J. Rosena,2

aThe Musculoskeletal Laboratory, Maine Medical Center Research Institute, Scarborough, ME 04074; bDepartment of Biology, University of Virginia, Charlottesville, VA 22904; cDepartment of Orthopaedic Surgery, Center for Diabetes and Endocrine Research, University of Toledo Medical Center, Toledo, OH 43614; d The Jackson Laboratory, Bar Harbor, ME 04609; eDepartment of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229; fDepartment of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT 06520; and gDepartment of Medicine, University of North Carolina, School of Medicine, Chapel Hill, NC 27599

Edited* by John T. Potts, Massachusetts General Hospital, Charlestown, MA, and approved May 4, 2010 (received for review January 20, 2010)

Abstract: 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.

Author contributions: M.K. and C.J.R. designed research; M.K., N.D., M.R.G., C.A.-B., and N.G. performed research; M.K., C.B.G., B.L.-C., N.D., M.R.G., S.K., C.A.-B., N.G., M.C.H., M.L.A., D.R.C., and C.J.R. analyzed data; and M.K. and C.J.R. wrote the paper.

1Present address: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1000788107/-/DCSupplemental.

2To whom correspondence should be addressed. E-mail: crofen{at}gmail.com.

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