Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone

Abstract

11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within adipose tissue and liver. 11HSD1 inhibitors may enhance insulin sensitivity in type 2 diabetes and be most efficacious in obesity when 11HSD1 is increased in subcutaneous adipose biopsies. We examined the regeneration of cortisol in vivo in obesity, and the effects of the 11HSD1 inhibitor carbenoxolone. We compared six lean and six obese men and performed a randomized, placebo-controlled crossover study of carbenoxolone in obese men. 11␤-Hydroxysteroid dehydrogenase type 1 (11HSD1) is a microsomal enzyme expressed in many tissues, including liver and adipose tissue (1). It catalyzes the regeneration of the active glucocorticoid cortisol from its inactive 11-keto metabolite cortisone. This intracellular generation of cortisol plays a key role in amplifying glucocorticoid receptor activation independently of the level of cortisol in the circulating plasma. Its potential importance is illustrated in animal models. Transgenic mice that overexpress 11HSD1 by approximately threefold selectively in adipocytes under the AP2 promoter/enhancer (2,3) develop about a twofold increase in intraadipose glucocorticoid levels despite no change in plasma levels, which are controlled by a compensatory fall in ACTH secretion. This results in central obesity together with hyperinsulinemia, hyperglycemia, hyperlipidemia, and hypertension. Mice with similar overexpression of 11HSD1 in liver under the ApoE promoter develop insulin resistance, dyslipidemia, and hypertension without obesity (4). Conversely, 11HSD1 knockout mice on a high-fat diet are protected from obesity, hyperglycemia, and dyslipidemia and redistribute fat to peripheral rather than central fat depots (5-7). Moreover, inbred rodent models of obesity and diabetes show tissue-specific dysregulation of 11HSD1 (2,8,9); most commonly, 11HSD1 is reduced in liver but increased in adipose tissue. These findings substantiate the hypothesis that increased intra-adipose glucocorticoid regeneration by 11HSD1 contributes to obesity and its metabolic complications.Whether increased 11HSD1 levels have a similar importance in human obesity and associated type 2 diabetes is controversial (10). The conventional measure of 11HSD1 is the ratio of urinary cortisol to cortisone metabolites, which is inconsistently altered in obesity (11-16) and diabetes (17)(18)(19). However, this ratio may be confounded by the activity of other enzymes (e.g., 11HSD type 2, 5␣-and 5␤-reductase) that differ in obesity, and is insensitive to the tissue-specific changes in 11HSD1 that have been observed in animals. Hepatic 11HSD1 has been assessed in humans by measuring the conversion of an oral dose of cortisone into cortisol in peripheral plasma after "first pass" metabolism, and is consistently reduced in obesity

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…Further studies have directly confirmed increased 11 -HSD1 activity using tissue microdialysis in obese subcutaneous adipose tissue (Sandeep et al, 2005). Recent studies suggest that in some cases 11 -HSD1 mRNA levels are also increased in visceral omental adipose tissue of obese women and are a strong predictor of fat cell size in this visceral depot (Desbriere et al, 2006, Michailidou et al, 2007, Paulsen et al, 2007.…”

“…This notion was strengthened by more recent studies using specific 11 -HSD-1 inhibitors which reduced hyperglycaemia in diabetic mice (Alberts et al, 2002). Human adipose tissue microdialysis (Sandeep et al, 2005, Tomlinson et al, 2007 have shown some efificay of carbenoxolone in adipose. Further, carbenoxolone can reduce liver triglyceride production, improve glucose tolerance and ameliorate atherogenesis with combined inhibition of liver and adipose 11 -HSD1 in dyslipidaemic or high fat dietinduced obese rodents (Nuotio-Antar, 2007, Taylor et al, 2008.…”

“…To date, pharmacological intervention with 11 -HSD1 inhibition in vivo has shown the full range of protective metabolic, anti-obesity, anti-inflammatory and antiatherogenic effects with a growing body of evidence for beneficial effects in man (Walker et al, 1995, Andrews et al, 2003, Sandeep et al, 2005, Tomlinson et al, 2007, see Hughes et al, 2008 for an extensive review).…”

Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning

“…Indeed, cortisol concentrations in the portal vein (Aldhahi et al 2004) or superficial epigastric veins (Katz et al 1999) have not been shown to be greater than those in the arterial circulation, although cortisone levels in veins draining adipose tissue are lower. It is known, however, that infusion of cortisone directly into subcutaneous adipose tissue results in local production of cortisol (Sandeep et al 2005). …”

Augmentation of 11β‐hydroxysteroid dehydrogenase type 1 in LPS‐activated J774.1 macrophages – Role of 11β‐HSD1 in pro‐inflammatory properties in macrophages

“…Carbenoxolone [4,14,15], a non-selective inhibitor for 11b-HSD1 and 11b-HSD2 was obtained from Sigma (St. Louis, MO, USA). Recently-developed 11b-HSD1 selective inhibitors, 3-(1-adamantyl)-5,6,7,8,9,10-hexahydro [1,2,4] triazolo [4,3-a] azocine trifluoroacetate salt (WO03/065983, Merck Co., USA) (inhibitor A for short, unless otherwise indicated) [16] and 2,4,6-trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl) benzenesulfonamide (BVT-3498, Biovitrum, Sweden) (inhibitor B for short, unless otherwise indicated) [17,18] were synthesized according to the patent information.…”