Aims/hypothesisGlucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.MethodsLean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.ResultsCentral administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Conclusions/interpretationCollectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

BACKGROUND Continued androgen receptor (AR) signaling constitutes a key target for treatment in metastatic castration-resistant prostate cancer (CRPC). Studies have identified 11-ketotestosterone (11KT) as a potent AR agonist, but it is unknown if 11KT is present at physiologically relevant concentrations in patients with CRPC to drive AR activation. The goal of this study was to investigate the circulating steroid metabolome including all active androgens in patients with CRPC. METHODS Patients with metastatic CRPC ( n = 29) starting a new line of systemic therapy were included. Sequential plasma samples were obtained for measurement of circulating steroid concentrations by multisteroid profiling employing liquid chromatography–tandem mass spectrometry. Metastatic tumor biopsy samples were obtained at baseline and subjected to RNA sequencing. RESULTS 11KT was the most abundant circulating active androgen in 97% of patients with CRPC (median 0.39 nmol/L, range: 0.03–2.39 nmol/L), constituting 60% (IQR 43%–79%) of the total active androgen (TA) pool. Treatment with glucocorticoids reduced 11KT by 84% (49%–89%) and testosterone by 68% (38%–79%). Circulating TA concentrations at baseline were associated with a distinct intratumor gene expression signature comprising AR-regulated genes. CONCLUSION The potent AR agonist 11KT is the predominant circulating active androgen in patients with CRPC and, therefore, one of the potential drivers of AR activation in CRPC. Assessment of androgen status should be extended to include 11KT, as current clinical approaches likely underestimate androgen abundance in patients with CRPC. TRIAL REGISTRATION Netherlands Trial Register: NL5625 (NTR5732). FUNDING Daniel den Hoed Foundation and Wellcome Trust (Investigator Award WT209492/Z/17/Z).

Steroid hormones play a central role in the maintenance and progression of prostate cancer. The androgen receptor is the primary driver of tumor cell proliferation and is activated by the androgens testosterone and 5α-dihydrotestosterone. Inhibition of this pathway through medical or surgical castration improves survival in the majority of advanced prostate cancer patients. However, conversion of adrenal androgen precursors and alternative steroidogenic pathways have been found to contribute to tumor progression and resistance to treatment. The emergence of highly accurate detection methods allows us to study steroidogenic mechanisms in more detail, even after treatment with potent steroidogenic inhibitors such as the CYP17A1 inhibitor abiraterone. A clear overview of steroid hormone levels in patients throughout the local, metastatic and castration-resistant stages of prostate cancer and treatment modalities is key toward a better understanding of their role in tumor progression and treatment resistance. In this review,

BACKGROUND: Androgen receptor (AR) ligand-binding domain (LBD) mutations occur in ~20% of all castration-resistant prostate cancer (CRPC) patients. These mutations confer ligand promiscuity, but the affinity for many steroid hormone pathway intermediates is unknown. In this study, we investigated the stimulation of clinically relevant AR-LBD mutants by endogenous and exogenous steroid hormones present in CRPC patients to unravel their potential contribution to AR pathway reactivation. METHODS: A meta-analysis of studies reporting untargeted analysis of AR mutants was performed to identify clinically relevant AR-LBD mutations. Using luciferase reporter and quantitative fluorescent microscopy, these AR mutants were screened for sensitivity for various endogenous steroids and synthetic glucocorticoids used in the treatment of CRPC. RESULTS:The meta-analysis revealed that AR L702H (3.4%), AR H875Y (4.9%), and AR T878A (4.4%) were the most prevalent AR-LBD mutations across 1614 CRPC patients from 21 unique studies. Testosterone (EC50: 0.22 nmol/L) and 11-ketotestosterone (11KT, EC50: 0.74 nmol/L) displayed subnanomolar affinity for AR WT . The p.H875Y mutation selectively increased sensitivity of the AR for 11KT (EC50: 0.15 nmol/L, p < 0.05 vs AR WT ), whereas p.L702H decreased sensitivity for 11KT by almost 50-fold. While cortisol and prednisolone both stimulate AR L702H , dexamethasone importantly does not. CONCLUSION: Both testosterone and 11KT effectively contribute to AR WT activation, while selective sensitization positions 11KT as a more prominent activator of AR H875Y . Dexamethasone may be a suitable alternative to prednisolone and should be explored in patients bearing the AR L702H .

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