Endocrine Abstracts

Introduction: Glucocorticoid excess (GE) causes severe metabolic dysfunction within skeletal muscle (SM) which includes reduced muscle accrual and increased proteolysis. The NAD+ metabolome is crucial for SM health and metabolic function, however, whether this is disrupted by GE remains unknown.Methods: Male and female C57BL/6J mice (n=12) were treated with a vehicle control or corticosterone (100 mg/l) ad libitum via drinking water for 3 weeks ...

Objective: Therapeutic glucocorticoids (GCs) are used to treat chronic inflammatory disease, due to their anti-inflammatory effects. Despite their efficacy, chronic exposure to GCs elicits undesirable side effects, including muscle atrophy. 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs within muscle, is induced by inflammation, and has previously shown to drive GC-induced muscle wasting. We examined the role of 11β-HSD1 in mediating muscle wasting i...

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an NADPH-dependant oxo-reductase located in the sarcoplasmic reticulum (SR) lumen of skeletal muscle. Here it generates active glucocorticoids to regulate permissive and adaptive metabolism, and can mediate the pathological effects of glucocorticoid excess. Hexose-6-phosphate dehydrogenase (H6PD) in the SR interacts with 11β-HSD1 to generate an appropriate NADPH/NADP+ ratio to support activity. H6PD depletion...

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), whilst effective at suppressing inflammation and inflammatory muscle loss, also cause myopathy with prolonged administration. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a bidirectional GC activating enzyme, potently up-regulated by inflammation within mesenchymal derived tissues. We assessed the regulation of this enzyme with inflammation in muscle and examined its functi...

Nicotinamide adenine dinucleotide (NAD+) levels increase during metabolic stress, which acts as a consumed substrate by, amongst other proteins, the sirtuins, which adapt transcriptional programmes to increase energy availability and regulate insulin sensitivity. Thus, maintaining appropriate skeletal muscle NAD+ availability is critical for regulating systemic energy homeostasis. In order to gain better insight into ageing muscle NAD+ dynamics we used ta...

Glucocorticoids (GC) are critical to stress adaptation but in excess (Cushing’s syndrome) drive metabolic dysfunction. 11β-hydroxysteroid dehydrogenase type 1(11β-HSD1) amplifies intracellular GC signaling with 11β-HSD1KO mice protected from the side-effects of GC excess. Brown adipose tissue (BAT) function is impaired by GC’s, which repress UCP1 and beta-adrenergic stimulated thermogenesis. Identifying mechanisms regulating BAT function is important a...

Steroid hormones and bile acids are potent regulators of metabolic phenotype. The enzyme 5β-Reductase (AKR1D1) has a crucial role in bile acid synthesis and also generates 5β-reduced dihydrosteroid metabolites, regulating intra-cellular steroid availability though the clearance of cortisol, testosterone, androstenedione and progesterone. As AKR1D1 sits at the interface of bile acid synthesis and steroid metabolism, we have hypothesised that it plays a key role in met...

Both therapeutic glucocorticoids (GCs) and chronic inflammation are powerful inducers of systemic bone loss, resulting in osteoporosis and increased morbidity. Whilst GCs suppress inflammation, it is unclear how these factors interact to determine net bone metabolism. We investigated the balance between osteo-protective and osteo-destructive properties of GCs in the TNF-tg model of chronic inflammatory disease. Wild-type (WT) and TNF-tg mice were treated with corticosterone (1...

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and papilloedema, diagnosed primarily in obese women of reproductive age, with the incidence rising with the global epidemic of obesity. Weight-loss lowers ICP and treats IIH. No mechanism explains the link between obesity and raised ICP. We hypothesise that adipose tissue from IIH patients has a metabolically distinct profile that contributes to raised ICP. Our previous data demo...

Steroid hormones and bile acids are potent regulators of metabolic phenotype. The enzyme 5β-reductase (AKR1D1) has a crucial role in bile acid synthesis and also generates 5β-reduced dihydrosteroid metabolites, regulating intra-cellular steroid availability though the clearance of cortisol, testosterone, androstenedione, and progesterone. As AKR1D1 sits at the interface of bile acid synthesis and steroid metabolism, we have hypothesised that it plays a key role in me...