This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart 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 Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chan, G. K. Articles by Karaplis, A. C. Search for Related Content PubMed PubMed Citation Articles by Chan, G. K. Articles by Karaplis, A. C.

PTHrP Inhibits Adipocyte Differentiation by Down-Regulating PPAR Activity via a MAPK-Dependent Pathway

Division of Endocrinology, Department of Medicine, McGill University (G.K.C., R.A.D., A.C.K.), and Lady Davis Institute for Medical Research, Montréal, Québec, Canada H3T 1E2; and Calcium Research Laboratory, Department of Medicine, McGill University Health Center and McGill University (G.K.C., R.A.D., I.B., D.G.), Montréal, Québec, Canada H3A 1A1

Address all correspondence and requests for reprints to: Andrew C. Karaplis, M.D., Ph.D., Lady Davis Institute for Medical Research, Department of Medicine, McGill University, Montréal, Québec, Canada H3T 1E2. E-mail: akarapli{at}ldi.jgh.mcgill.ca

We examined the capacity of PTHrP to modulate the terminal differentiation of the preadipocytic cell line, 3T3-L1. These cells express endogenous PTHrP and its receptor, but expression levels were undetectable after differentiation into mature adipocytes. Cells stably overexpressing PTHrP failed to differentiate when induced to undergo adipogenesis and proliferated at a faster rate. MAPK activity was elevated in PTHrP-transfected 3T3-L1 cells, and treatment with the PKA inhibitor H-8 decreased this activity. Inhibition of MAPK kinase with PD098059 permitted terminal differentiation of PTHrP-transfected 3T3-L1 cells to proceed. Although PPAR gene expression levels remained relatively constant in the PTHrP-transfected cells, PPAR phosphorylation was enhanced. Furthermore, the capacity of PPAR to stimulate transcription in the presence of troglitazone was diminished by PTHrP. Expression of the PPAR-regulated adipocytespecific gene aP2 transiently rose and then fell in PTHrP-transfected cells. These results indicate that PTHrP can increase MAPK activity in 3T3-L1 cells via the PKA pathway, thereby enhancing PPAR phosphorylation. This modification can inactivate the transcriptional enhancing activity of PPAR and diminish the expression of adipocyte-specific genes. These studies therefore demonstrate that PTHrP may inhibit the terminal differentiation of preadipocytes and describe a molecular pathway by which this action can be achieved.

This article has been cited by other articles:

				N. Bhattacharya, J. M. Dufour, M.-N. Vo, J. Okita, R. Okita, and K. H. Kim Differential Effects of Phthalates on the Testis and the Liver Biol Reprod, March 1, 2005; 72(3): 745 - 754. [Abstract] [Full Text] [PDF]

				C. Chen, A. J. Koh, N. S. Datta, J. Zhang, E. T. Keller, G. Xiao, R. T. Franceschi, N. J. D'Silva, and L. K. McCauley Impact of the Mitogen-activated Protein Kinase Pathway on Parathyroid Hormone-related Protein Actions in Osteoblasts J. Biol. Chem., July 9, 2004; 279(28): 29121 - 29129. [Abstract] [Full Text] [PDF]

				B. Zingarelli, M. Sheehan, P. W. Hake, M. O'Connor, A. Denenberg, and J. A. Cook Peroxisome Proliferator Activator Receptor-{gamma} Ligands, 15-Deoxy-{Delta}12,14-Prostaglandin J2 and Ciglitazone, Reduce Systemic Inflammation in Polymicrobial Sepsis by Modulation of Signal Transduction Pathways J. Immunol., December 15, 2003; 171(12): 6827 - 6837. [Abstract] [Full Text] [PDF]

				R. K. Petersen, C. Jorgensen, A. C. Rustan, L. Froyland, K. Muller-Decker, G. Furstenberger, R. K. Berge, K. Kristiansen, and L. Madsen Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases J. Lipid Res., December 1, 2003; 44(12): 2320 - 2330. [Abstract] [Full Text] [PDF]

				G. K. Chan, D. Miao, R. Deckelbaum, I. Bolivar, A. Karaplis, and D. Goltzman Parathyroid Hormone-Related Peptide Interacts with Bone Morphogenetic Protein 2 to Increase Osteoblastogenesis and Decrease Adipogenesis in Pluripotent C3H10T1/2 Mesenchymal Cells Endocrinology, December 1, 2003; 144(12): 5511 - 5520. [Abstract] [Full Text] [PDF]

				A. J. Entingh, C. M. Taniguchi, and C. R. Kahn Bi-directional Regulation of Brown Fat Adipogenesis by the Insulin Receptor J. Biol. Chem., August 29, 2003; 278(35): 33377 - 33383. [Abstract] [Full Text] [PDF]

				K. M. Jung, K. S. Park, J. H. Oh, S. Y. Jung, K. H. Yang, Y. S. Song, D. J. Son, Y. H. Park, Y. P. Yun, M. K. Lee, et al. Activation of p38 Mitogen-Activated Protein Kinase and Activator Protein-1 during the Promotion of Neurite Extension of PC-12 Cells by 15-Deoxy-Delta 12,14-prostaglandin J2 Mol. Pharmacol., March 1, 2003; 63(3): 607 - 616. [Abstract] [Full Text] [PDF]

				Z.-C. Dang, V. Audinot, S. E. Papapoulos, J. A. Boutin, and C. W. G. M. Lowik Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) as a Molecular Target for the Soy Phytoestrogen Genistein J. Biol. Chem., January 3, 2003; 278(2): 962 - 967. [Abstract] [Full Text] [PDF]

				D. Prusty, B.-H. Park, K. E. Davis, and S. R. Farmer Activation of MEK/ERK Signaling Promotes Adipogenesis by Enhancing Peroxisome Proliferator-activated Receptor gamma (PPARgamma ) and C/EBPalpha Gene Expression during the Differentiation of 3T3-L1 Preadipocytes J. Biol. Chem., November 22, 2002; 277(48): 46226 - 46232. [Abstract] [Full Text] [PDF]