Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

Abstract

Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

Effects of High-fat Diets on Biochemical Profiles and Morpho- Quantitative Characteristics of C57BL/6 Mice Adrenal Glands

“…This combination of increased urinary excretion of cortisol metabolites with a hyperdynamic HPA axis and normal cortisol levels is likely to be explained by the increased peripheral metabolic clearance of cortisol. In fact, increased cortisol clearance has been documented repeatedly in obesity (Strain et al, 1980;Lottenberg et al, 1998;Stimson et al, 2009Stimson et al, , 2011. The aforementioned could explain the results of the studies carried out by Auvinen et al and ours, regarding the decrease in plasma levels of diurnal corticosterone in mice fed with HFDs.…”

“…As noted above, glucocorticoid levels in obesity show different results, however, many studies support the idea that exits an increase in the overall activity of cortisol (Stomby et al, 2014). Supporting this, the excretion of glucocorticoid metabolites in the urine is elevated in obese people (Andrew et al, 1998).…”

Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review

“…Nonetheless, we acknowledge that obtaining tissue biopsies, particularly hepatic tissue biopsies, or invasive cold isotope infusion methods are difficult and carry a greater participant burden than measuring other peripheral cortisol parameters. Furthermore, initial phase 2 clinical trials suggest that inhibiting 11␤-HSD1 in humans, although broadly having the same beneficial effects as in preclinical models, is not sufficiently efficacious to be a sole therapy for conditions associated cortisol irregularities, notably type 2 diabetes and obesity (Stomby et al, 2014). Whilst this may reflect a lesser importance of cortisol regeneration in human adipocytes, the inevitable "compensatory" HPA axis activation with 11␤-HSD1 inhibition (to overcome loss of bulk regeneration of cortisol) could indicate alternative HPA-driven products that ameliorate the effects of local enzyme inhibition in vivo.…”

Cibler la voie métabolique du cortisol comme action thérapeutique dans le diabète de type 2

“…• Comment expliquer ces résultats finalement assez décevants chez l'homme, alors que les premiers essais chez le rongeur, en particulier la souris, s'étaient révélés particulièrement prometteurs [24] ? Cet échec relatif pourrait résulter d'un manque de sélectivité des inhibiteurs de la 11βHSD1 utilisés jusqu'à présent, qui exercent aussi une action sur la 11β-réductase [35].…”

“…Les premiers essais chez l'homme ont fait appel à la carbénoxolone, mais les résultats ont été peu encourageants dans plusieurs essais pilotes chez des sujets avec une certaine insulinorésistance et la présence ou non d'un DT2 [24]. Les raisons invoquées pour cet échec relatif étaient que la carbénoxolone n'est pas un inhibiteur puissant de la 11βHSD1 et que, par ailleurs, elle n'exerce pas une action suffisamment sélective, puisque qu'elle inhibe également l'enzyme 11β-hydroxystéroïde déshy-drogénase de type 2 (11βHSD2) [24] (figure 1). L'industrie pharmaceutique a tenté de développer des inhibiteurs synthétiques, plus puissants et plus sélectifs, de la 11βHSD1 [25,26] [27].…”