The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome

Abstract

The cortisol regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies tissue glucocorticoid levels, particularly in the liver and adipose tissue. The importance of this enzyme in causing metabolic disease was highlighted by transgenic mice which over- or under-expressed 11β-HSD1; consequently, selective 11β-HSD1 inhibitors have been widely developed as novel agents to treat obesity and type 2 diabetes mellitus (T2DM). This review focuses on the importance of 11β-HSD1 in humans which has been more difficult to ascertain. The recent development of a deuterated cortisol tracer has allowed us to quantify in vivo cortisol production by 11β-HSD1. These results have been surprising, as cortisol production rates by 11β-HSD1 are at least equivalent to that of the adrenal glands. The vast majority of this production is by the liver (>90%) with a smaller contribution from subcutaneous adipose tissue and possibly skeletal muscle, but with no detectable production from visceral adipose tissue. This tracer has also allowed us to quantify the tissue-specific regulation of 11β-HSD1 observed in obesity and obesity-associated T2DM, determine the likely basis for this dysregulation, and identify obese patients with T2DM as the group most likely to benefit from selective inhibition of 11β-HSD1. Some of these inhibitors have now reached Phase II clinical development, demonstrating efficacy in the treatment of T2DM. We review these results and discuss whether selective 11β-HSD1 inhibitors are likely to be an important new therapy for metabolic disease.

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review

“…Pharmacological inhibition of 11b-HSD1 with the anti-ulcer drug carbenoxolone has provided evidence that cortisol regeneration influences insulin sensitivity, particularly glycogen turnover in healthy human subjects and in patients with type 2 diabetes [207,208]. This corroborated the notion that the enzyme may be an attractive option to treat the metabolic disease [108,190,202,212,213]. Moreover, 11 -HSD1 gene knock-out (11 -HSD1-/-) mice exhibited cardioprotective phenotype with improved glucose tolerance and lipid profile, reduced weight and visceral fat accumulation in condition of chronic high-fat feeding [190,200,201,214].…”

“…11 -HSD1-knock-out mice fed on a high-fat diet are protected from obesity and metabolic complications [199][200][201]. Recently, polymorphisms in HSD11B1, the gene encoding 11 -HSD1, have been associated with components of the metabolic syndrome [186,[202][203][204][205]. Moreover, subjects with single nucleotide polymorphisms (SNPs) in HSD11B1 gene exhibit increased adipose 11 -HSD1 expression and increased whole-body 11 -HSD1 activity, associated with increased prevalence of the metabolic syndrome.…”

Adipocytes, aldosterone and obesity-related hypertension

“…This question remains under debate as reports showed that adipocytes do not have significant 11b-HSD2 activity and yet maintain a relatively high level of 11b-HSD1 activity, allowing glucocorticoids to be the main ligand for adipocyte-MR (Kargi et al 2014). Moreover, visceral obesity and metabolic syndrome have been associated with increased adipose 11b-HSD1 activity, further increasing intra-adipocyte cortisol concentrations (Morton et al 2004, Koska et al 2006, Stimson & Walker 2007.…”

The Metabolic Implications of Glucocorticoids in a High-Fat Diet Setting and the Counter-Effects of Exercise

“…The glucocorticoid/glucocorticoid receptor (GC/GR) interaction plays a critical role in maintaining overall glucose homeostasis, in a number of tissues including the brain and periphery, as maintenance of systemic carbohydrate metabolism requires complex regulation between various peripheral organs in addition to the central nervous system. Subtle alterations in both cortisol secretion and/or tissue-specific reactivation of less active GCs (i.e., cortisone) to a more active form (i.e., cortisol), via the prereceptor enzyme 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), are a possible link between GC biology and the development of insulin resistance [17] and metabolic syndrome/type 2 diabetes mellitus (T2DM) [18,19,20]. …”