11β‐Hydroxysteroid dehydrogenase type 1: relevance of its modulation in the pathophysiology of obesity, the metabolic syndrome and type 2 diabetes mellitus

Abstract

Recent evidence strongly argues for a pathogenic role of glucocorticoids and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in obesity and the metabolic syndrome, a cluster of risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus (T2DM) that includes insulin resistance (IR), dyslipidaemia, hypertension and visceral obesity. This has been partially prompted not only by the striking clinical resemblances between the metabolic syndrome and Cushing's syndrome (a state characterized by hypercortisolism that associates with metabolic syndrome components) but also from monogenic rodent models for the metabolic syndrome (e.g. the leptin-deficient ob/ob mouse or the leptin-resistant Zucker rat) that display overall increased secretion of glucocorticoids. However, systemic circulating glucocorticoids are not elevated in obese patients and/or patients with metabolic syndrome. The study of the role of 11β-HSD system shed light on this conundrum, showing that local glucocorticoids are finely regulated in a tissue-specific manner at the pre-receptor level. The system comprises two microsomal enzymes that either activate cortisone to cortisol (11β-HSD1) or inactivate cortisol to cortisone (11β-HSD2). Transgenic rodent models, knockout (KO) for HSD11B1 or with HSD11B1 or HSD11B2 overexpression, specifically targeted to the liver or adipose tissue, have been developed and helped unravel the currently undisputable role of the enzymes in metabolic syndrome pathophysiology, in each of its isolated components and in their prevention. In the transgenic HSD11B1 overexpressing models, different features of the metabolic syndrome and obesity are replicated. HSD11B1 gene deficiency or HSD11B2 gene overexpression associates with improvements in the metabolic profile. In face of these demonstrations, research efforts are now being turned both into the inhibition of 11β-HSD1 as a possible pharmacological target and into the role of dietary habits on the establishment or the prevention of the metabolic syndrome, obesity and T2DM through 11β-HSD1 modulation. We intend to review and discuss 11β-HSD1 and obesity, the metabolic syndrome and T2DM and to highlight the potential of its inhibition for therapeutic or prophylactic approaches in those metabolic diseases.

Importance of the 11β-hydroxysteroid dehydrogenase enzyme in clinical disorders

“…Ugyanakkor a visceralis zsírszövetben is fokozott a 11-β-HSD-1-aktivitás, és a HSD11B1-expresszió korrelál a hexóz-6-foszfát-dehidrogenáz mRNS-szintjével [9]. Muñoz és mtsai igazolták, hogy a subcutan zsírszövet HSD11B1 mRNS-tartalma nagyobb, mint a visceralis zsírszövet HSD11B1 mRNS-tartalma, ami arra utalhat, hogy a subcutan zsírszövetnek nagyobb szerepe lehet az elhízásban [1], ezen belül is a centrális elhízás kialakulásában [1,10].…”

“…Riportergén-konstrukció segítségével Draper és munkatársai igazolták, hogy a 83,557insA (rs45487298, amely 100%-ban kapcsolt a szintén a 3-as intronban található rs12086634-gyel) és a H6PD gén rs6688832-es (R453Q) polimorfi zmusa kortizonreduktáz-hiányt (CRD) okoz a 11-β-HSD-1 enzim NADPH-ellátásának gátlása miatt [1,9]. San Millán és munkatársai azonban arra a következtetésre jutottak, hogy a két polimorfi zmus együttes előfordulása nem minden esetben jár együtt kortizonreduktáz-hiánnyal [12].…”

“…A különböző inhibitorok hatásmechaniz-musának vizsgálata során megállapították, hogy a szulfonamidszerkezetű vegyületek a szubsztrát kompetitív inhibitorai, míg a triazolszerkezetű vegyületek nemcsak elfoglalják a katalitikus helyet, hanem módosítják is annak egy részét [2,9].…”

Novel Aspects of Glucocorticoids Actions on Energy Homeostasis and Hydromineral Balance

“…Accordingly, LPS is detectable in the circulation of both healthy and obese individuals, but it may transiently raises following energy-rich meals. It has also been shown that the intake of fat-rich diet acts as an inducer of chronic stress, elevating basal glucocorticoid levels and enhancing HPA axis responses to stress (Tannenbaum et al, 1997), suggesting that glucocorticoids are likely to participate in the pathogenesis of metabolic syndrome and obesity (Milagro et al, 2007;Paternain et al, 2011), even though obese individuals and patients with metabolic syndrome do not necessarily show elevated systemic glucocorticoid concentrations (Pereira et al, 2012).…”

Resveratrol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rat adipose microsomes

“…Intracellular glucocorticoid levels are regulated by 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1) and 11b-HSD2. 11b-HSD1, which is abundantly expressed in the adipose tissue and in the liver, acts as an oxoreductase converting inactive cortisone into bioactive cortisol in humans (11-dehydrocorticosterone into corticosterone in rodents) (Pereira et al 2012), whereas 11b-HSD2 catalyzes the reverse reaction to 11b-HSD1, mainly in the kidney. Recently, evidence has been accumulated that intracellular glucocorticoid amplification in adipocytes by 11b-HSD1 contributes to central obesity and, consequently, promotes metabolic diseases in experimental animals (Masuzaki et al 2001) and humans (Bujalska et al 1997, Wake et al 2003.…”