Endocrine Abstracts

We all live in an oscillating environment driven by the Earth’s rotation. This imposes predictable patterns of light and dark, to which almost all of life responds. There is a survival advantage in anticipating such environmental change, which has led to evolution of the autonomous circadian clock.The circadian clock controls up to 40% of biochemical pathways, often acting to control a rate-limiting enzymatic step. Therefore, design and interpretati...

We all live in an oscillating environment driven by the Earth’s rotation. This imposes predictable patterns of light and dark, to which almost all of life responds. There is a survival advantage in anticipating such environmental change, which has led to evolution of the autonomous circadian clock.The circadian clock controls up to 40% of biochemical pathways, often acting to control a rate-limiting enzymatic step. Therefore, design and interpretati...

The glucocorticoid receptor (GR) is a nuclear receptor, a major drug target, and the end point of the hypothalamic-pituitary-adrenal axis. Glucocorticoids (GC) are essential for life, but in excess cause disordered energy metabolism, including increased weight gain, adiposity and hepatosteatosis; all programmes modulated by the circadian clock. Secretion of GC is regulated by the circadian clock, but could their actions be also? Here, using mouse as a model, we found that whil...

The glucocorticoid receptor (GR) is a ligand activated transcription factor, serving to regulate both energy metabolic and immune functions. The natural endogenous glucocorticoid in humans is cortisol, but a variety of synthetic molecules have been developed to treat inflammatory disease. These synthetic ligands offer new insights into how the GR works, and how it can be manipulated. Novel, non-steroidal GR agonists specifically alter the GR LBD structure at the HSP90 binding ...

The circadian clock is a key regulator of immune responses. Both circulating and resident immune cells possess intrinsic timers, which act to impart time-of-day variation in their function. It is now becoming evident that the circadian clock is also critically involved in regulating the function of endogenous anti-inflammatory glucocorticoid hormones. Consequently, we see variation in an animal’s inflammatory responses dependent on the time the stimulus was delivered. Thi...

The metastasis related methyltransferase 1 (Merm1), originally designated WBSCR22, is implicated in cancer through H3K9 methylation and silencing of the tumour-suppressor Zac1 gene. Activated GR is a transcription factor with chromatin remodelling activity, and so the functional interaction between GR, and Merm1 was determined. Merm1 consistently potentiated GR transactivation of TAT3-Luc in HeLa cells. This was dependent on the SAM and methyltransferase domains of Merm1. Merm...

Glucocorticoids (GCs) are potent anti-inflammatory agents, but a variable therapeutic response occurs. We have used microarray analysis to explore the basis for inter-individual differences in the GC sensitivity of a healthy volunteer population, and identified genes predictive of response to GCs. Three such discriminating genes were then selected to be investigated for their potential to interact with the Glucocorticoid Receptor (GR). These are the Bone Morphogenetic Protein ...

One in five people in the UK is affected by lung disease, along with millions more worldwide. Glucocorticoids represent the most utilized anti-inflammatory therapy for the treatment of pulmonary inflammation, however a subset of patients exist which do not respond to therapeutically relevant doses.The non-ciliated bronchial epithelial (Clara) cells have been identified as key mediators of the pulmonary inflammatory response. The glucocorticoid receptor (...

Adiponectin, an exclusive adipose-derived hormone, circulates at high concentration, and exerts metabolic effects. Adiponectin levels in the circulation correlate negatively with BMI, and low adiponectin concentrations are associated with the low grade inflammation and metabolic dysfunction that accompanies obesity. Adiponectin has been reported to have potent anti-inflammatory activities, and to exert these effects by regulating macrophage function. The mechanism of adiponect...

Glucocorticoids (Gc) are the most potent anti-inflammatory agents known. A major factor limiting their clinical use is the wide variation in responsiveness to treatment between individuals and over time. Generating a reversible model of Gc resistance in vitro that will mimic the cellular microenvironment in vivo is critical in (i) defining biomarkers that predict patient steroid responsiveness; (ii) provide a model to screen new GR modulators capable of potentiating GR ...