Novel model to study the physiological effects of temporary or prolonged sex steroid deficiency in male mice

Kim, Na Ri; Khalil, R; David, Karel; LʼAbbate, Antonio; Schollaert, Dieter; Deboel, Ludo; Herck, Erik Van; Nele, Wardenier; Cools, Martine; Decallonne, Brigitte; Claessens, Frank; Dubois, Vanessa; Vanderschueren, Dirk

doi:10.1152/ajpendo.00401.2020

Cited by 9 publications

(13 citation statements)

References 42 publications

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“…The primer sequences are listed in Appendix Table S1. Before performing ChIP on AR Lmon/Y kidneys, all antibodies were first validated using kidneys from chemically castrated male WT mice with or without T supplementation described in Kim et al (2020, 2021) (Appendix Fig S5A–K).…”

Section: Methodsmentioning

confidence: 99%

The androgen receptor depends on ligand‐binding domain dimerization for transcriptional activation

et al. 2021

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Whereas dimerization of the DNA‐binding domain of the androgen receptor (AR) plays an evident role in recognizing bipartite response elements, the contribution of the dimerization of the ligand‐binding domain (LBD) to the correct functioning of the AR remains unclear. Here, we describe a mouse model with disrupted dimerization of the AR LBD (ARLmon/Y). The disruptive effect of the mutation is demonstrated by the feminized phenotype, absence of male accessory sex glands, and strongly affected spermatogenesis, despite high circulating levels of testosterone. Testosterone replacement studies in orchidectomized mice demonstrate that androgen‐regulated transcriptomes in ARLmon/Y mice are completely lost. The mutated AR still translocates to the nucleus and binds chromatin, but does not bind to specific AR binding sites. In vitro studies reveal that the mutation in the LBD dimer interface also affects other AR functions such as DNA binding, ligand binding, and co‐regulator binding. In conclusion, LBD dimerization is crucial for the development of AR‐dependent tissues through its role in transcriptional regulation in vivo. Our findings identify AR LBD dimerization as a possible target for AR inhibition.

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Section: Methodsmentioning

confidence: 99%

The androgen receptor depends on ligand‐binding domain dimerization for transcriptional activation

et al. 2021

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“…Both global AR-knockout mice, as well as bone cell specific AR-knockout mouse models show reduced bone mass (Almeida et al, 2017). Castration, surgically or chemically, leads to rapid bone loss as well, mainly characterized by a loss in trabecular number without major influence on trabecular thickness and by a decrease in cortical thickness (Khalil et al, 2020;Kim et al, 2020). Additionally, androgen replacement therapy, either with T or DHT, has been shown to be able to prevent this bone loss in different rodent models (Khalil et al, 2020;Vanderschueren et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Androgen therapy does not prevent bone loss and arterial calcifications in male rats with chronic kidney disease

David

Dubois

Verhulst

et al. 2023

Journal of Endocrinology

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Patients suffering from chronic kidney disease (CKD) often experience bone loss and arterial calcifications. It is unclear if hypogonadism contributes to the development of these complications, and whether androgen therapy might prevent them. Male adult rats were randomized into 4 groups. The first group received standard chow (Control), while three other groups were fed a 0.25% adenine/low vitamin K diet (CKD). Two CKD groups were treated with testosterone (T) or dihydrotestosterone (DHT), whereas the control group and one CKD group received vehicle (VEH). CKD animals had 10-fold higher serum creatinine and more than 15-fold higher PTH-levels compared to controls. Serum T levels were more than 2-fold lower in the CKD-VEH group compared to Control-VEH and CKD-T groups. Seminal vesicle weight was reduced by 50% in CKD-VEH animals, and restored by T and DHT. CKD animals showed a low bone mass phenotype with decreased trabecular bone volume fraction and increased cortical porosity, which was not rescued by androgen treatment. Aortic calcification was much more prominent in CKD animals and not unequivocally prevented by androgens. Messenger RNA expression of the androgen receptor-responsive genes Acta1 and Col1a1 was reduced by CKD and stimulated by androgen treatment in levator ani muscle, but not in bone or aortic tissue. We conclude that adenine-induced CKD results in the development of hypogonadism in male rats. Androgen therapy is effective in restoring serum T levels and androgen-sensitive organ weights, but does not prevent bone loss or arterial calcifications, at least not in the presence of severe hyperparathyroidism.

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“…In experiment 2, mice were exposed to CD or control light–dark cycles for a total duration of 6 weeks. In addition, the mice received subcutaneous injections at days 1 and 29 with either vehicle ( n = 8 per group per sex) or gonadotropin‐releasing hormone (GnRH)‐antagonist degarelix (25 mg/kg; MedChemExpress, Monmouth Junction, New Jersey, USA) ( n = 8 per group per sex) to suppress the production and secretion of gonadal sex hormones as a less‐invasive alternative to orchiectomy and ovariectomy 15 . Voluntary physical activity was assessed between days 1–12 and days 23–34.…”

Section: Methodsmentioning

confidence: 99%

Circadian disruption impairs glucose homeostasis in male but not in female mice and is dependent on gonadal sex hormones

et al. 2023

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Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropinreleasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.

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Novel model to study the physiological effects of temporary or prolonged sex steroid deficiency in male mice

Cited by 9 publications

References 42 publications

The androgen receptor depends on ligand‐binding domain dimerization for transcriptional activation

The androgen receptor depends on ligand‐binding domain dimerization for transcriptional activation

Androgen therapy does not prevent bone loss and arterial calcifications in male rats with chronic kidney disease

Circadian disruption impairs glucose homeostasis in male but not in female mice and is dependent on gonadal sex hormones

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