Glucocorticoids regulate adipose-tissue differentiation, function, and distribution, and when present in excess, cause central obesity. Cushing's syndrome is associated with central obesity and insulin resistance with features of the metabolic syndrome. But plasma cortisol levels are consistently normal in common obesity. Omental tissue has been shown to express 11 β HSD1 enzyme and hence has the ability to generate glucocorticoids locally. Common obesity has thus been described as Cushing's syndrome of the omentum. It is possible that excessive glucocorticoid receptor activation could contribute towards development of the obese state.
Till recently, it was thought that the plasma levels of steroids and their plasma binding proteins (CBG) as well as the density of steroid receptors in tissues might be the major determinants of activity of steroids in the various tissues. The emphasis is now shifting towards the pre-receptor metabolism of the ligands (cortisol) by tissue specific enzymes as 11 β HSD. This can be considered analogous to the modulatory effects exerted by 5 alpha reductase in androgen actions, 5'monodeiodinase in thyroid hormone actions, and aromatase and 17 β hydroxysteroid dehydrogenases in oestrogen actions at the tissue level.
Till recently, it was thought that the plasma levels of steroids and their plasma binding proteins (CBG) as well as the density of steroid receptors in tissues might be the major determinants of activity of steroids in the various tissues. The emphasis is now shifting towards the pre-receptor metabolism of the ligands (cortisol) by tissue specific enzymes as 11 β HSD. This can be considered analogous to the modulatory effects exerted by 5 alpha reductase in androgen actions, 5'monodeiodinase in thyroid hormone actions, and aromatase and 17 β hydroxysteroid dehydrogenases in oestrogen actions at the tissue level.
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Actions of 11 β HSD 1
11 β HSD 1 (11 β-hydroxysteroid dehydrogenase) facilitates the regeneration of active cortisol and corticosterone (11 hydroxy glucocorticoids) from their inactive 11-keto forms namely cortisone and 11 dehydrocorticosterone Endocrinology. 2001 Apr;142(4):1371-6. by its oxidoreductase (11 β reductase) action. The reverse reaction facilitating inactivation of cortisol to cortisone is also effected by the 11 β HSD1 enzyme through 11 β dehydrogenation. Endocrinology. 1988 Nov;123(5):2390-8. In contrast 11 β HSD2 demonstrates the dehydrogenase action only . |
11 β HSD 1 at the tissue level
Although this bidirectional interconversion between inactive and active forms was initially thought to be involved in maintaining adequate plasma levels of the hormones, it is now increasingly recognised that these reactions may play tissue specific roles in modulating steroid activity locally. The selectivity for aldosterone at the non-selective mineralocorticoid receptors in the distal nephron even in the face of high glucocorticoid levels was thus explained by the rapid inactivation of glucocorticoids in these cells by 11 β HSD2, Science. 1988 Oct 28;242(4878):583-5. Endocrinology. 1993 Jun;132(6):2614-21. the importance of which is clearly demonstrated by the excess glucocorticoid activity exerted via these mineralocorticoid receptors in the congenital absence of the 11 β HSD2 enzyme J Clin Endocrinol Metab. 1979 Nov;49(5):757-64. or its inhibition by liquorice based molecules. Lancet. 1987 Oct 10;2(8563):821-4 While 11 β HSD2 expression was mainly in aldosterone selective target tissues as the distal nephron, colon ,sweat glands and placenta suggesting its predominant role in ensuring mineralocorticoid selectivity at mineralocorticoid receptors, the role of 11 β HSD1 isoenzyme and its expression in various tissues gained interest at a later stage. 11 β HSD1 is highly expressed in liver, adipose tissue and the CNS where it maintains adequate levels of cortisol within cells even in the presence of low circulating cortisol levels, Lancet. 1997 Apr 26;349(9060):1210-3 through a predominant β reductase activity. Human omental adipose stromal cells (ASCs) can generate glucocorticoid locally through the expression of 11 β-HSD1, converting inactive cortisone to cortisol by its reductase action. J Clin Endocrinol Metab. 2002 Mar;87(3):1205-10. |
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Regulators of 11 β HSD1
Clearly a preponderance of 11 β reductase (corticosterone regenerating) action over 11 β dehydrogenation (corticosterone inactivating) action would result in higher tissue levels of the active steroids. In fact the presence of the reduced co substrate NADPH Nat Genet. 2003 Aug;34(4):434-9. as well as the intact-ness of the cells have been thought to determine the direction of conversion. 11 β HSD 1 action is also regulated by glucocorticoids, J Steroid Biochem Mol Biol. 1999 Mar;68(5-6):245-50. thyroid hormones, sex steroids, growth hormone, IGF-1, insulin, cytokines Vitam Horm. 1999;57:249-324. and PPAR alpha agonists as fibrates. Biochem Biophys Res Commun. 2000 Dec 20;279(2):330-6. Reduction of 11 β HSD 1 induced glucocorticoid target gene expression in liver by fibrates might indirectly account for their beneficial triglyceride lowering effect. Adipokines do not seem to influence 11 beta HSD1 regulation. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. |
Effects of 11 β HSD 1 knock out 11 β HSD1 knock out mice have low intracellular glucocorticoid levels and are resistant to development of obesity and insulin resistance, Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924-9. while transgenic mice over-expressing 11 β HSD have elevated intracellular glucocorticoid levels with development of the metabolic syndrome. Science. 2001 Dec 7;294(5549):2166-70. Note that in the liver, glucocorticoids antagonise insulin action by stimulating the rate limiting enzyme for gluconeogenesis, namely PEPCK (phosphoenol-pyruvate carboxykinase) . In 11 β HSD1 knock out mice, PEPCK induction is impaired with a reduced hyperglycaemic response to stress. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924-9. Similar improvement in glycaemia by reduction in insulin resistance through the inhibition of 11 β HSD1 has been demonstrated in humans as well. J Clin Endocrinol Metab. 1995 Nov;80(11):3155-9. In β HSD1 knock out mice, the inability to regenerate glucocorticoids in the periphery results in impairment of the negative feedback to the pituitary and hypothalamic axis, resulting in increased HPA activity resulting in adrenocortical hypertrophy. Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924-9. 11 β HSD1 knock out mice have normal vascular function in contrast to 11 β HSD2 knock out mice which has endothelial dysfunction. Cortisol impairs cholinergic vasodilation in the vessels Am J Hypertens. 2000 Nov;13(11):1155-60 which might be offset by nitric oxide dependent mechanism influenced by 11 β HSD. There is thus a need to further delineate the individual roles of these iso enzymes at the vascular level. |
11 Β HSD and obesity
Leptin resistant Zucker obese rats have impaired 11 β HSD 1 in the liver with increased activity in the omental adipose tissue. Endocrinology. 2000 Feb;141(2):560-3. Dysregulation of 11β HSD1 in human obesity has been described and seems to be tissue specific. Increasing BMI is associated with impaired 11β-HSD1 activity, with the degree of impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. This down-regulation of 11 β HSD1 activity in the obese could be protective against development of insulin resistance. Type 2 diabetic patients do not show this BMI related change in 11 β HSD1 activity J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack of down-regulation of 11 β HSD1 in obese patients could facilitate development of diabetes.
Like the genetically obese Leptin resistant Zucker rats, obese humans also demonstrate impairment of hepatic 11 β HSD1 activity, resulting in decreased reactivation of corticosteroids, J Clin Endocrinol Metab. 1999 Mar;84(3):1022-7 while 11 β HSD1 activity in subcutaneous abdominal adipose tissue is increased. J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21 This increase in 11 β HSD1 in adipose tissue might explain the proliferation of fat tissue and adverse metabolic effects in obesity. But studies in diet- induced obesity in wistar rats demonstrated a decrease in hepatic as well as adipose tissue 11 β HSD1 levels in response to high fat diet presumably as a compensatory response. Endocrinology. 2005 Feb;146(2):913-9 Thus diet-induced obesity has not been shown to result in excess activation of corticosteroids in the adipose tissue in contrast to genetically obese mice. Although a role for this enzymatic pathway in the aetiology of common obesity remains far from proved, there definitely exists a potential for manipulation of the 11 β HSD1 enzyme locally in adipose tissue to effect favourable metabolic changes without influencing circulating cortisol levels. Further hope is generated by the fact that growth hormone replacement in growth hormone deficient patients results in reduction of body fat along with lowered ratio of cortisol to cortisone in keeping with 11 β HSD1 inhibition. Clin Endocrinol (Oxf). 1994 Nov;41(5):639-48.
Leptin resistant Zucker obese rats have impaired 11 β HSD 1 in the liver with increased activity in the omental adipose tissue. Endocrinology. 2000 Feb;141(2):560-3. Dysregulation of 11β HSD1 in human obesity has been described and seems to be tissue specific. Increasing BMI is associated with impaired 11β-HSD1 activity, with the degree of impairment correlating with visceral fat mass. J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61. This down-regulation of 11 β HSD1 activity in the obese could be protective against development of insulin resistance. Type 2 diabetic patients do not show this BMI related change in 11 β HSD1 activity J Clin Endocrinol Metab. 2004 Sep;89(9):4755-61 and it can be postulated that a lack of down-regulation of 11 β HSD1 in obese patients could facilitate development of diabetes.
Like the genetically obese Leptin resistant Zucker rats, obese humans also demonstrate impairment of hepatic 11 β HSD1 activity, resulting in decreased reactivation of corticosteroids, J Clin Endocrinol Metab. 1999 Mar;84(3):1022-7 while 11 β HSD1 activity in subcutaneous abdominal adipose tissue is increased. J Clin Endocrinol Metab. 2001 Mar;86(3):1418-21 This increase in 11 β HSD1 in adipose tissue might explain the proliferation of fat tissue and adverse metabolic effects in obesity. But studies in diet- induced obesity in wistar rats demonstrated a decrease in hepatic as well as adipose tissue 11 β HSD1 levels in response to high fat diet presumably as a compensatory response. Endocrinology. 2005 Feb;146(2):913-9 Thus diet-induced obesity has not been shown to result in excess activation of corticosteroids in the adipose tissue in contrast to genetically obese mice. Although a role for this enzymatic pathway in the aetiology of common obesity remains far from proved, there definitely exists a potential for manipulation of the 11 β HSD1 enzyme locally in adipose tissue to effect favourable metabolic changes without influencing circulating cortisol levels. Further hope is generated by the fact that growth hormone replacement in growth hormone deficient patients results in reduction of body fat along with lowered ratio of cortisol to cortisone in keeping with 11 β HSD1 inhibition. Clin Endocrinol (Oxf). 1994 Nov;41(5):639-48.