Endocrine Abstracts

Tissue-level regeneration of active glucocorticoids (GC) by the intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) now represents a promising therapeutic target for the treatment of metabolic syndrome. Proof of principle came largely from our transgenic animal models of altered tissue GC action, which delineated 11β-HSD1 as a major determinant of intracellular GC exposure and a molecular link between ‘Cushingoid’ and idiopathic obe...

Introduction: Glucocorticoids are vital for regulating metabolic processes, as well as use in medical treatments. However chronic glucocorticoid excess is known to cause negative metabolic effects including hyperglycaemia, muscle atrophy and fat accumulation. The effect on energy metabolism and metabolic rate remains undefined and merits investigation in both male and female mice.Methods: 20 male and 20 female C57BL/6J mice were randomly assigned to a co...

Background: During fetal development, the heart switches substrate preference from glucose to fatty acids, such that in the adult heart, 50–70% of ATP is derived from fatty acid oxidation. What triggers this switch is currently unclear. In vivo, the late gestation rise in glucocorticoid levels is essential for structural and functional maturation of the fetal heart. Glucocorticoid treatment of fetal cardiomyocytes induces express...

Background: During fetal development, the heart switches substrate preference from glucose to fatty acids, such that in the adult heart, 50–70% of ATP is derived from fatty acid oxidation. What triggers this switch is currently unclear. In vivo, the late gestation rise in glucocorticoid levels is essential for structural and functional maturation of the fetal heart. Glucocorticoid treatment of fetal cardiomyocytes induces express...

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), regenerates active glucocorticoids (cortisol, corticosterone) from inert substrates (cortisone, 11-dehydrocorticosterone) and has been implicated in the pathogenesis of the metabolic syndrome. 11β-HSD1 expression is increased in adipose tissue and decreased in liver in human and rodent obesity. Paradoxically, in chronically high fat-fed mice 11β-HSD1 is down-regulated in adipose tissue. Transcri...

The global prevalence of obesity continues to rise, creating a growing need for new effective medicines. Selective targeting of visceral obesity (fat around the internal organs) would be particularly advantageous because it carries a greater risk for cardiometabolic diseases. The ectonucleotide pyrophosphatase (ENPP) enzyme family participates in several pathological conditions including diabetes (ENPP1, and ENPP2, also known as autotaxin) and vascular dysfunction (ENPP3-4). O...

Endometriosis is a chronic incurable hormone dependent condition characterized by growth of endometrial tissue in sites outside the uterus: 30–40% of women with endometriosis have sub/infertility however the underlying cause is unknown. We have previously demonstrated that steroid-induced differentiation of endometrial stromal cells (hESC) (decidualisation) is associated with increased expression of metabolic genes that are thought to be essential to support the implantin...

Insulin-resistant diabetes is characterised by progressive pancreatic β-cell dysfunction. Elevated pancreatic islet activity of the intracellular glucocorticoid amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) was hypothesized to drive this process in genetically obese rodents. To determine the direct effects of elevated 11β-HSD1 on β-cell function in diabetes in vivo we created a transgenic model overexpressing 11β-HSD1...

Deficiency of the intracellular glucocorticoid (GC) reactivating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) invokes compensatory activation of the HPA axis. Nevertheless, 11β-HSD1−/− mice resist dietary-induced obesity indicating that target tissues are protected from GC actions. Since endocrine adaptation to diet is mediated by altered HPA activity, we investigated whether the adrenal response to high fat (HF) diet is compr...

Obesity, particularly abdominal (visceral) obesity, is a major risk factor for development of the metabolic syndrome. Human and animal studies have shown elevated intra-adipose glucocorticoid-action in obesity and suggest that increased glucocorticoid receptor (GR) density may be an important determinant of visceral adiposity. We have tested this hypothesis in transgenic (Tg) mice in which adipose GR levels have been increased or decreased, by expression of “sense” o...