11β-HSD1 contributes to age-related metabolic decline in male mice.

The aged phenotype shares several metabolic similarities with that of circulatory glucocorticoid excess (Cushing's syndrome), including type 2 diabetes, obesity, hypertension, and myopathy. We hypothesise that local tissue generation of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts 11-dehydrocorticosterone to active corticosterone in rodents (corticosterone to cortisol in man), plays a role in driving age-related chronic disease. In this study, we have examined the impact of ageing on glucocorticoid metabolism, insulin tolerance, adiposity, muscle strength, and blood pressure in both wildtype (WT) and transgenic male mice with a global deletion of 11β-HSD1 (11β-HSD1-/-) following 4 months high-fat feeding.

Regulation of 11β-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients.

Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushing's syndrome (glucocorticoid excess) - notably visceral obesity, insulin resistance, muscle myopathy and increased vascular mortality. Within key metabolic tissues, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid, cortisol (11-dehydrocorticosterone and corticosterone in rodents respectively), and thus amplifies local glucocorticoid action. We hypothesize that 11β-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11β-HSD1 within key metabolic tissues (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease.

The CRH-Transgenic Cushingoid Mouse Is a Model of Glucocorticoid-Induced Osteoporosis.

Glucocorticoids (GCs) have unparalleled anti-inflammatory and immunosuppressive properties, which accounts for their widespread prescription and use. Unfortunately, a limitation to GC therapy is a wide range of negative side effects including Cushing's syndrome, a disease characterized by metabolic abnormalities including muscle wasting and osteoporosis. GC-induced osteoporosis occurs in 30% to 50% of patients on GC therapy and thus, represents an important area of study.

11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice.

Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can amplify circulating GC concentrations.

25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.

Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers.

11β-Hydroxysteroid dehydrogenase type 1 within muscle protects against the adverse effects of local inflammation.

Muscle wasting is a common feature of inflammatory myopathies. Glucocorticoids (GCs), although 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 that is potently upregulated by inflammation within mesenchymal-derived tissues.

Male 11β-HSD1 Knockout Mice Fed Trans-Fats and Fructose Are Not Protected From Metabolic Syndrome or Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) defines a spectrum of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis and is regarded as the hepatic manifestation of the metabolic syndrome. Glucocorticoids can promote steatosis by stimulating lipolysis within adipose tissue, free fatty acid delivery to liver and hepatic de novo lipogenesis. Glucocorticoids can be reactivated in liver through 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme activity.

Glucocorticoids and 11β-HSD1 are major regulators of intramyocellular protein metabolism.

The adverse metabolic effects of prescribed and endogenous glucocorticoid excess, 'Cushing's syndrome', create a significant health burden. While skeletal muscle atrophy and resultant myopathy is a clinical feature, the molecular mechanisms underpinning these changes are not fully defined. We have characterized the impact of glucocorticoids upon key metabolic pathways and processes regulating muscle size and mass including: protein synthesis, protein degradation, and myoblast proliferation in both murine C2C12 and human primary myotube cultures.

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing's syndrome.

Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have 'Cushingoid' side effects including visceral obesity, muscle myopathy, hypertension, insulin resistance, type 2 diabetes mellitus, osteoporosis, and hepatic steatosis. These features are replicated in patients with much rarer endogenous glucocorticoid (GC) excess (Cushing's syndrome), which has devastating consequences if left untreated. Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited.

Gender-Specific Differences in Skeletal Muscle 11β-HSD1 Expression Across Healthy Aging.

Context: Cushing's syndrome is characterized by marked changes in body composition (sarcopenia, obesity, and osteoporosis) that have similarities with those seen in aging. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts glucocorticoids to their active form (cortisone to cortisol in humans), resulting in local tissue amplification of effect.

Objective: To evaluate 11β-HSD1 expression and activity with age, specifically in muscle.

11β-Hydroxysteroid dehydrogenase-1 is involved in bile acid homeostasis by modulating fatty acid transport protein-5 in the liver of mice.

11β-Hydroxysteroid dehydrogenase-1 (11β-HSD1) plays a key role in glucocorticoid receptor (GR) activation. Besides, it metabolizes some oxysterols and bile acids (BAs). The GR regulates BA homeostasis; however, the impact of impaired 11β-HSD1 activity remained unknown.

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess.

Loss of 5α-reductase type 1 accelerates the development of hepatic steatosis but protects against hepatocellular carcinoma in male mice.

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability.

Impaired oxidoreduction by 11β-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; however, biomarkers to assess its activity in vivo are still lacking. Recent in vitro experiments suggested that human 11β-HSD1 metabolizes the secondary bile acid 7-oxolithocholic acid (7-oxoLCA) to chenodeoxycholic acid (CDCA) and minor amounts of ursodeoxycholic acid (UDCA). Here, we provide evidence from in vitro and in vivo studies for a major role of 11β-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species.

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects.

Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs).

Regulation of lipid metabolism by glucocorticoids and 11β-HSD1 in skeletal muscle.

The prevalences of insulin resistance and type 2 diabetes mellitus are rising dramatically, and, as a consequence, there is an urgent need to understand the pathogenesis underpinning these conditions to develop new and more efficacious treatments. We have tested the hypothesis that glucocorticoid (GC)-mediated changes in insulin sensitivity may be associated with changes in lipid flux. Furthermore, prereceptor modulation of GC availability by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) may represent a critical regulatory step.

11β-Hydroxysteroid dehydrogenase 1: translational and therapeutic aspects.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts the inactive glucocorticoid cortisone and its active form cortisol. It is widely expressed and, although bidirectional, in vivo it functions predominantly as an oxoreductase, generating active glucocorticoid. This allows glucocorticoid receptor activation to be regulated at a prereceptor level in a tissue-specific manner.

Hormonal regulation of lipogenesis.

Obesity has reached epidemic proportions with severe heath consequences including type 2 diabetes, nonalcoholic fatty liver disease, and premature cardiovascular mortality. Understanding the biological processes that govern fat deposition in a tissue-specific manner is therefore crucial if we are to try to design novel and efficacious treatments that might limit fat accumulation and improve metabolic phenotype and clinical prognosis. Lipid accumulation within a given cell type represents a balance between synthesis, mobilization, and utilization.

Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver.

Inflammatory regulation of glucocorticoid metabolism in mesenchymal stromal cells.

Objective: Tissue glucocorticoid (GC) levels are regulated by the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). This enzyme is expressed in cells and tissues arising from mesenchymal stromal cells. Proinflammatory cytokines dramatically increase expression of 11β-HSD1 in stromal cells, an effect that has been implicated in inflammatory arthritis, osteoporosis, obesity, and myopathy.

Regulation of lipogenesis by glucocorticoids and insulin in human adipose tissue.

Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes.

11beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of type 2 diabetes.

Importance Of The Field: The prevalence of obesity and type 2 diabetes is rising and reaching pandemic proportions. For this reason, identification of novel therapeutic targets is urgently needed.

Areas Covered In This Review: The endoluminal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes glucocorticoid activation in key metabolic tissues including skeletal muscle, liver and adipose tissue, and is strongly implicated in the pathogenesis of obesity, type 2 diabetes and the metabolic syndrome.

11beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle.

Objective: Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity.