This Article Full Text Full Text (PDF) Supplemental Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager NURSA Molecule Pages Link Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chao, L. C. Articles by Tontonoz, P. Search for Related Content PubMed PubMed Citation Articles by Chao, L. C. Articles by Tontonoz, P.

Inhibition of Adipocyte Differentiation by Nur77, Nurr1, and Nor1

Howard Hughes Medical Institute (L.C.C., S.J.B., C.J.V., K.W., P.T.), Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095-1662; and The Center for Diabetes, Endocrinology and Metabolism (L.C.C.), Childrens Hospital Los Angeles, University of Southern California, Los Angeles, California 90027

Address all correspondence and requests for reprints to: Peter Tontonoz M.D., Ph.D., Howard Hughes Medical Institute, University of California Los Angeles School of Medicine, Box 951662, Los Angeles, California 90095-1662. E-mail: ptontonoz{at}mednet.ucla.edu.

Members of the nuclear receptor 4A (NR4A) subgroup of nuclear receptors have been implicated in the regulation of glucose and lipid metabolism in insulin-sensitive tissues such as liver and skeletal muscle. However, their function in adipocytes is not well defined. Previous studies have reported that these receptors are rapidly up-regulated after treatment of 3T3-L1 preadipocytes with an adipogenic cocktail. We show here that although Nur77 expression is acutely induced by cAMP agonists in 3T3-L1 cells, it is not induced by other adipogenic stimuli, such as peroxisome proliferator-activated receptor- ligands, nor is it induced during the differentiation of 3T3-F442A preadipocytes, suggesting that Nur77 induction is not an obligatory feature of preadipocyte differentiation. We further demonstrate that inflammatory signals that antagonize differentiation, such as TNF and lipopolysaccharide, acutely induce Nur77 expression both in vitro and in vivo. We also show that NR4A expression in adipose tissue is responsive to fasting/refeeding. Retroviral transduction of each of the NR4A receptors (Nur77, Nurr1, and NOR1) into either 3T3-L1 or 3T3-F442A preadipocytes potently inhibits adipogenesis. Interestingly, NR4A-mediated inhibition of adipogenesis cannot be rescued by peroxisome proliferator-activated receptor- overexpression or activation. Transcriptional profiling of Nur77-expressing preadipocytes led to the identification of gap-junction protein 1 (Gja1) and tolloid-like 1 (Tll1) as Nur77-responsive genes. Remarkably, retroviral expression of either Gja1 or Tll1 in 3T3-L1 preadipocytes also inhibited adipocyte differentiation, implicating these genes as potential mediators of Nur77’s effects on adipogenesis. Finally, we show that Nur77 expression inhibits mitotic clonal expansion of preadipocytes, providing an additional mechanism by which Nur77 may inhibit adipogenesis.

NURSA Molecule Pages Link:

Nuclear Receptors:   NGFIB  |  NURR1  |  NOR1

This article has been cited by other articles:

				K. W. Park, H. Waki, W.-K. Kim, B. S. J. Davies, S. G. Young, F. Parhami, and P. Tontonoz The Small Molecule Phenamil Induces Osteoblast Differentiation and Mineralization Mol. Cell. Biol., July 15, 2009; 29(14): 3905 - 3914. [Abstract] [Full Text] [PDF]