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Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with ß-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors

Division of Endocrinology, Metabolism, and Molecular Medicine (R.S., J.N.A., W.E.T., M.B., N.F.G.-C., S.B.), Charles R. Drew University of Medicine and Science, Los Angeles, California 90059; Beth Israel Deaconess Medical Center and Harvard Medical School (X.Y.), Boston, Massachusetts 02215; and Section of Endocrinology, Diabetes, and Nutrition (S.B.), Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Rajan Singh, Ph.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Charles R. Drew School of Medicine, 1731 East 120th Street, Augustus F. Hawkins Building, Los Angeles, California 90059. 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)/ß-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 differentiate to form fat cells in adipogenic medium. We found that these cells express AR and that testosterone and dihydrotestosterone dose-dependently inhibited adipogenic differentiation as analyzed by Oil Red O staining and down-regulation of CCAAT/enhancer binding protein- and - and peroxisome proliferator-activated receptor-2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of ß-catenin and AR. Immunoprecipitation studies demonstrated association of ß-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 VP-16 did not inhibit the expression of CCAAT/enhancer binding protein- in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of ß-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.

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