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Testosterone Inhibits Adipogenic Differentiation in 3T3-L1 Cells: Nuclear Translocation of Androgen Receptor Complex with β-Catenin and T-Cell Factor 4 May Bypass Canonical Wnt Signaling to Down-Regulate Adipogenic Transcription Factors
Open accessAbstract
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)/β-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-α and -δ and peroxisome proliferator-activated receptor-γ2 protein and mRNA. These inhibitory effects of androgens were partially blocked by flutamide or bicalutamide. Androgen treatment was associated with nuclear translocation of β-catenin and AR. Immunoprecipitation studies demonstrated association of β-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-α in the absence of androgens. Testosterone and dihydrotestosterone inhibit adipocyte differentiation in vitro through an AR-mediated nuclear translocation of β-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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“Testosterone inhibits the expression of the activity of lipoprotein lipase, the main enzymatic regulator of triglyceride uptake in the fat cell, preferentially in abdominal fat (28, 29).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [29]
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Metadata
- Authors
- Singh, R., Artaza, J. N., Taylor, W. E., Braga, M., Yuan, X., Gonzalez-Cadavid, N. F., & Bhasin, S.
- Affiliations
- Charles R. Drew University of Medicine and Science (US)
- Beth Israel Deaconess Medical Center (US)
- 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
- Boston Medical Center (US)
- Corresponding author
- Singh, Rajan
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2006-01-01
- Volume
- 147
- Issue
- 1
- Pages
- 141-154
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC4417624
- OpenAlex
- W2064549818
- Cited by
- 369
- References
- 57
- Citations by year
- 2026: 6 · 2025: 14 · 2024: 13 · 2023: 5 · 2022: 14 · 2021: 6 · 2020: 17 · 2019: 7 · 2018: 13 · 2017: 27 · 2016: 9 · 2015: 30 · 2014: 20 · 2013: 29 · 2012: 21
- FWCI
- 6.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1p20md000545-01, 5u01dk070431-11)
- National Institute on Aging (SC1AG033407)
- National Institute of General Medical Sciences (S06GM068510)
- National Institute of Diabetes and Digestive and Kidney Diseases (1R01 DK 59627-01, U01-DK-070431, R01DK070534, R01DK059627, 1R01DK70431-01)
- National Center for Research Resources (G12 RR 03026, G12RR003026)
- National Institute on Minority Health and Health Disparities (1P20MD000545-02, P20 MD000545)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD041748-0, U54HD041748, R01HD043348)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- testosterone, adipogenesis, androgen receptor, β-catenin, T-cell factor 4, Wnt signaling, 3T3-L1 cells, preadipocytes, C/EBPα, C/EBPδ, PPARγ, nuclear translocation, flutamide, bicalutamide, fat mass, androgen supplementation
- MeSH terms
- Adipose Tissue, Animals, Cell Differentiation, Cell Nucleus, Gene Expression Regulation, Receptors, Androgen, RNA, Messenger, Testosterone, Transcription Factors, Transcription, Genetic, Signal Transduction, 3T3 Cells, Adipocytes, Reverse Transcriptase Polymerase Chain Reaction, Protein Transport, Wnt Proteins, beta Catenin, Mice, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein
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