Endocrine Abstracts

Although obesity affects men and women, the risks of associated metabolic disturbances (e.g. type 2 diabetes) differ between the sexes. Altered peripheral glucocorticoid metabolism may underpin the metabolic consequences of obesity; however, most research exploring this has focused on male animals. This study used a mouse model to investigate the hypothesis that alterations in glucocorticoid metabolism caused by diet-induced obesity (DIO) will be more profound in males than in...

Anti-inflammatory salicylates improve insulin sensitivity, however the mechanism remains unclear. We have observed down-regulation of the glucocorticoid regenerating enzyme 11β-hydroxysteroid dehydrogenase 1 (11βHSD1) by salicylates in cultured adipocytes and in human adipose tissue after oral salsalate therapy, consistent with known transcriptional regulation of 11βHSD1 by pro-inflammatory cytokines. Since inhibition of 11βHSD1 improves insulin sensitivity...

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive glucocorticoid to their active form (cortisone to cortisol in humans, 11-dehydrocorticosterone (11-DHC) to corticosterone in mice), and is dependent upon the presence of cofactor NADPH generated by the enzyme hexose-6-phosphate (H6PDH) for its activity. The 11β-HSD1/H6PDH system is implicated in the pathogenesis of the metabolic syndrome by generating tissue specific glucocorticoid excess. The ...

6-Phosphogluconate dehydrogenase (6PGDH) is the third enzyme of the oxidative phase of the pentose phosphate pathway. The cytosolic form of this pathway is well characterised, but the details and significance of the endoplasmic reticulum (ER) version are only beginning to be understood. We have previously identified hexose-6-phosphate dehydrogenase (H6PDH), which catalyses the first two steps of this pathway within the lumen of the ER, as a pivotal regulator of ER reductases s...

Glucocorticoids are highly detrimental to skin integrity and function both when used locally for anti-inflammatory treatments and during conditions of raised systemic concentrations such as Cushing’s syndrome. Many of the adverse effects of glucocorticoids on skin are also symptoms associated with natural intrinsic aging and extrinsic photoaging.Locally, glucocorticoid availability is regulated independently of circulating levels by 11β-hydroxy...

Murine 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyses the conversion of inactive 11-dehydrocorticosterone (A) to active corticosterone (B) and plays a key role in metabolic homeostasis. The directionality of this enzyme is dependent upon the presence of NADPH, a cofactor produced by hexose-6-phosphate dehydrogenase (H6PDH). In accord with this, H6PDH KO mice have no reductase and increased dehydrogenase activity of 11βHSD1. Interestingly, H6PDH KO m...

Glucocorticoids possess potent angiostatic properties. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) amplifies local glucocorticoid action in a tissue-specific manner, and we have shown that inactivation of this enzyme enhances angiogenesis within sponges implanted subcutaneously, wounds and infarcted myocardium. 11βHSD1 is present within ocular tissues but its role in the pathogenesis of proliferative retinopathy is unknown. We hypothesised that inhibition ...

NADPH generated by hexose-6-phosphate dehydrogenase (H6PDH) within the lumen of the endoplasmic reticulum (ER) drives the reductase activity of 11β-hydroxysteroid dehydrogenase type 1 (11-βHSD1) allowing the production of active glucocorticoids. H6PDH knockout (H6PDHKO) mice develop a vacuolating myopathy, reduced muscle mass and display activation of the ER stress response. However, the role of glucocorticoids and 11β-HSD1 in the myopathy phenotype is not clear...

Recent investigations have suggested that 11ß-hydroxysteroid dehydrogenase-1 (11ßHSD1) activity influences development of atherosclerotic lesions and that pharmacological inhibition of this enzyme may have therapeutic benefits. Whilst these findings have been attributed to glucocorticoid metabolism, 11ßHSD1 also inter-converts 7-oxysterols (oxidized products of cholesterol which may promote atherogenesis). This study investigates whether metabolism of 7-oxystero...

The tachykinin neurokinin B (NKB) has prominent roles in neuroendocrine function, behaviour and the control of reproductive processes, yet little is known about its evolution, potential splice variants or the manner in which it is processed. Indeed, the cloning of human TAC3 in 2000 revealed a single gene transcript encoding a single precursor and single tachykinin. Here, we deduce the phylogenetic relationship of a family of NKB peptides, and identify novel TAC3...