Non-DNA binding-dependent androgen receptor pathway in fat (#213)
Our androgen receptor knockout (ARΔZF2) mouse model has an in-frame deletion of exon 3 of the AR1 which abolishes DNA binding-dependent AR actions, but retains non-DNA binding-dependent actions. ARΔZF2 male mice have increased subcutaneous and renal fat mass compared to wildtype (WT) males, but decreased total body mass. This phenotype differs from AR null mouse models which have a late onset obese phenotype, associated with increased fat mass and increased total body mass2, 3. To further investigate the non-DNA binding-dependent pathways in fat, we performed orchidectomy in ARΔZF2 male mice aged 7 weeks, to remove all endogenous androgens, and then treated mice with non-aromatisable dihydrotestosterone (DHT) or control implants for 10 weeks. Differences between control orchidectomised and DHT-treated orchidectomised ARΔZF2 males must arise through non-DNA binding-dependent AR pathways. We validated our orchidectomy surgery by showing that in WT orchidectomised males, seminal vesicles completely regressed, and kidney mass was decreased by 33% compared to sham-operated males (p<0.001). DHT treatment of orchidectomised males increased kidney mass to 13% above sham (p<0.001), suggesting a slightly supraphysiological androgen delivery. There was a mean difference of 13% in subcutaneous fat and 18% in renal fat in DHT-treated orchidectomised ARΔZF2 males compared to ARΔZF2 orchidectomised control males (n≥20/group), but these were not significant and the study was underpowered to determine if this difference was significant. The IL-6 gene, known to be repressed by the non-DNA binding-dependent AR pathway4 was not different between DHT-treated orchidectomised ARΔZF2 males and ARΔZF2 orchidectomised control males (n=12/group). However, Western analyses in subcutaneous fat showed that ERK phosphorylation was increased by 87% in DHT-treated orchidectomised ARΔZF2 males compared to orchidectomised control males (n=11/group). This data demonstrates a molecular role of non-DNA binding-dependent AR signalling in subcutaneous fat.
- Notini AJ et al. Genomic actions of the androgen receptor are required for normal male sexual differentiation in a mouse model. J Mol Endocrinol 35, 2005.
- Lin HY et al. Insulin and leptin resistance with hyperleptinemia in mice lacking androgen receptor. Diabetes 54, 2005.
- Sato T et al. Late onset of obesity in male androgen receptor-deficient (ARKO) mice. Biochem Biophys Res Commun 300, 2003.
- Keller ET et al. Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 271, 1996.