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Rôle de l’enzyme 11β-hydroxystéroïde-déshydrogénase de type 1 dans le risque métabolique associé à l’obésité

Role of 11β-hydroxysteroid-dehydrogenase type 1 in the metabolic risk associated with obesity

  • Article Scientifique / Scientific Article
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Obésité

Résumé

Certaines similitudes entre le syndrome métabolique associé à l’obésité abdominale et le syndrome de Cushing ont fait rechercher un excès tissulaire en glucocorticoïdes, même en l’absence de taux anormalement élevés dans le plasma. L’enzyme 11β-hydroxystéroïde-déshydrogénase de type 1 (11HSD1), qui convertit la cortisone (inactive) en cortisol (actif) dans les tissus cibles, présente une augmentation d’expression et d’activité en cas d’obésité, au moins dans certains tissus impliqués dans les régulations métaboliques, comme le tissu adipeux. Les données expérimentales obtenues sur des rongeurs mettent en évidence un lien direct entre l’apparition d’anomalies métaboliques et une augmentation d’activite de la 11HSD1 et entre un profil métabolique favorable et l’invalidation du gène codant pour cette enzyme chez des souris KO. L’administration d’inhibiteurs spécifiques de la 11HSD1 entraîne une amélioration des profils glucidiques et lipidiques, ainsi qu’une perte de poids, à condition que la 11HSD1 soit inhibée dans le tissu adipeux (plutôt que dans le foie). Des résultats préliminaires obtenus avec divers inhibiteurs, puissants et sélectifs, de la 11HSD1 ont révélé une diminution de l’insulinorésistance, une amélioration de la tolérance au glucose ou du contrôle glycémique et une amélioration du profil lipidique chez l’homme. Si ces résultats se confirment, les inhibiteurs sélectifs de la 11HSD1 pourraient représenter à l’avenir une nouvelle classe pharmacologique destinée à corriger les anomalies métaboliques associées à l’obésité, y compris le diabète de type 2.

Abstract

Similarities between metabolic syndrome associated with abdominal obesity and Cushing syndrome led to the search of excessive local tissue exposition to glucocorticoids at the cellular levels, despite normal circulating plasma levels of cortisol. To this respect, 11β-hydroxysteroid-dehydrogenase type 1 (11HSD1), which converts cortisone (inactive) to cortisol (active) in target tissues, raises much interest. Both increased expression and activity of this enzyme has been reported in presence of obesity, at least in some tissues that play a major role in metabolic regulations, such as adipose tissue. Experimental data in rodents showed a direct link between increased 11HSD1 activity and the development of metabolic disturbances. Furthermore, studies in mice KO for 11HSD1 demonstrated the potential of the inhibition of this enzyme to alleviate the metabolic abnormalities related to diet-induced obesity. The administration of specific inhibitors of 11HSD1 resulted in significant improvement of glucose and lipid profiles, together with a weight reduction, provided that 11HSD1 activity was blocked in the adipose tissue (rather than in the liver). Preliminary observations when various, potent and selective, inhibitors of 11HSD1 given in humans also showed a diminution of insulin resistance, an improvement of glucose tolerance or glucose control and an amelioration of lipid profile. In case of confirmation of such promising results, selective inhibitors of 11HSD1 might represent a new pharmacological class aiming at treating metabolic abnormalities associated with obesity, including type 2 diabetes.

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Authors and Affiliations

  1. Université de Liège, B-4000, Liège, Belgique

    A. Iovino, N. Paquot & A.J. Scheen

  2. Service de diabétologie, nutrition et maladies métaboliques, département de médecine, CHU Sart-Tilman, B-4000, Liège, Belgique

    N. Paquot & A.J. Scheen

  3. Unité de pharmacologie clinique, département de médecine, CHU Sart-Tilman, B-4000, Liège, Belgique

    A.J. Scheen

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Iovino, A., Paquot, N. & Scheen, A. Rôle de l’enzyme 11β-hydroxystéroïde-déshydrogénase de type 1 dans le risque métabolique associé à l’obésité. Obes 4, 181–188 (2009). https://doi.org/10.1007/s11690-009-0204-2

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