Marculescu, R. | bioRxiv Science

bioRxiv2020

Cold-mediated regulation of systemic retinol transport controls adipose tissue browning

Browning of white fat reduces obesity in many preclinical models. Vitamin A metabolites (retinoids) have been linked to thermogenic programming of adipose tissue (AT), however the physiologic importance of systemic retinoid metabolism for AT browning is unknown. Here we show that cold stimulation in mice and humans increases circulating retinol and its plasma transporter, retinol binding protein (RBP). Cold exposure shifts retinol abundance from liver towards subcutaneous white AT which correlates with enhanced thermogenic gene transcription. Cold-mediated retinoid flux is abrogated in Rbp deficient (Rbp-/-) mice and AT browning is dramatically impaired, which renders Rbp-/- mice cold intolerant. Rbp deficiency attenuates cold-induced lipid clearance due to decreased oxidative capacity. In humans, cold-mediated retinol increase is associated with enhanced lipid utilization. Retinol stimulation in primary human adipocytes promotes thermogenic gene expression and mitochondrial respiration. In conclusion, coordinated retinol delivery is essential for cold-induced thermogenic programming of white fat.

physiology↗

bioRxiv2019

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein -Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRa/TRb) in target tissues. We show in this study that low CRYM expression levels in PCa patient samples are associated with early BCR and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in PET/MRI imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3 and androgen-mediated signalling. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth. HighlightsO_LIThyroid and androgen hormone driven pathways in prostate cancer (PCa) are antagonized by - Crystallin (CRYM). C_LIO_LI[18F]fluoromethylcholine uptake and prognostic values in PCa correlate with CRYM protein levels. C_LIO_LIReduced CRYM expression predicts early biochemical recurrence (BCR) in PCa patients. C_LI

cancer biology↗