| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 22, 2004
Accepted on September 9, 2005
-Catenin and TCF4 may Bypass Canonical Wnt Signaling to Downregulate Adipogenic Transcription Factors
Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059; Beth Israel Deaconess Medical Center and Harvard Medical School, Boston; Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center
* To whom correspondence should be addressed. E-mail: rajansingh{at}mednet.ucla.edu.
Testosterone supplementation in men decreases fat mass; however, the mechanisms by which it inhibits fat mass are unknown. We hypothesized that testosterone inhibits adipogenic differentiation of preadipocytes by activation of androgen receptor (AR)/
-catenin interaction, and subsequent translocation of this complex to the nucleus thereby bypassing canonical Wnt signaling. We tested this hypothesis in 3T3-L1 cells that differentiates to form fat cells in adipogenic medium. We found that these cells express androgen receptor (AR), and testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil-Red O staining, and down regulation of C/EBP-
and -
and PPAR
2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of -catenin and AR. Immunoprecipitation studies demonstrated association of -catenin with AR and T-cell factor 4 (TCF4) in the presence of androgens. Transfection of TCF4 cDNA inhibited adipogenic differentiation; whereas, a dominant negative TCF4 cDNA construct induced adipogenesis and blocked testosterone's inhibitory effects. Our gene array analysis indicates that testosterone treatment led to activation of some Wnt target genes. Expression of constitutively activated AR fused with VP16 did not inhibit the expression of C/EBP- in the absence of androgens. Conclusions: Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of -catenin and activation of downstream Wnt signaling. These data provide evidence for a regulatory role for androgens in inhibiting adipogenic differentiation, and a mechanistic explanation consistent with the observed reduction in fat mass in men treated with androgens.
This article has been cited by other articles:
 |
|
 |
|
  P. Nantermet, S.-i. Harada, Y. Liu, S. Cheng, C. Johnson, Y. Yu, D. Kimme, D. Holder, P. Hodor, R. Phillips, et al. Gene Expression Analyses in Cynomolgus Monkeys Provides Mechanistic Insight into High-Density Lipoprotein-Cholesterol Reduction by Androgens in Primates Endocrinology, April 1, 2008; 149(4): 1551 - 1561. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Liu, J. D. Allen, J. T. Arnold, and M. R. Blackman Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells Carcinogenesis, April 1, 2008; 29(4): 816 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Handeli and J. A. Simon A small-molecule inhibitor of Tcf/{beta}-catenin signaling down-regulates PPAR{gamma} and PPAR{delta} activities Mol. Cancer Ther., March 1, 2008; 7(3): 521 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N Artaza, R. Singh, M. G Ferrini, M. Braga, J. Tsao, and N. F Gonzalez-Cadavid Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts J. Endocrinol., February 1, 2008; 196(2): 235 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Suh, E.-Y. Gong, J. B. Kim, I.-K. Lee, H.-S. Choi, and K. Lee Sterol Regulatory Element-Binding Protein-1c Represses the Transactivation of Androgen Receptor and Androgen-Dependent Growth of Prostatic Cells Mol. Cancer Res., February 1, 2008; 6(2): 314 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Kitagawa, W. J. Ray, H. Glantschnig, P. V. Nantermet, Y. Yu, C.-T. Leu, S.-i. Harada, S. Kato, and L. P. Freedman A Regulatory Circuit Mediating Convergence between Nurr1 Transcriptional Regulation and Wnt Signaling Mol. Cell. Biol., November 1, 2007; 27(21): 7486 - 7496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Montano, J. N. Flanagan, L. Jiang, P. Sebastiani, M. Rarick, N. K. LeBrasseur, C. A. Morris, R. Jasuja, and S. Bhasin Transcriptional Profiling of Testosterone-Regulated Genes in the Skeletal Muscle of Human Immunodeficiency Virus-Infected Men Experiencing Weight Loss J. Clin. Endocrinol. Metab., July 1, 2007; 92(7): 2793 - 2802. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Korner, J. Berndt, M. Stumvoll, W. Kiess, and P. Kovacs TCF7L2 Gene Polymorphisms Confer an Increased Risk for Early Impairment of Glucose Metabolism and Increased Height in Obese Children J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1956 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Corbould Chronic testosterone treatment induces selective insulin resistance in subcutaneous adipocytes of women J. Endocrinol., March 1, 2007; 192(3): 585 - 594. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Katznelson, M. W Robinson, C. L Coyle, H. Lee, and C. E Farrell Effects of modest testosterone supplementation and exercise for 12 weeks on body composition and quality of life in elderly men Eur. J. Endocrinol., December 1, 2006; 155(6): 867 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Blouin, C. Richard, G. Brochu, F.-S. Hould, S. Lebel, S. Marceau, S. Biron, V. Luu-The, and A. Tchernof Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men J. Endocrinol., December 1, 2006; 191(3): 637 - 649. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
