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Obesity Surgery
Published in: Obesity Surgery 3/2012

01-03-2012 | Clinical Research

Liver Upregulation of Genes Involved in Cortisol Production and Action Is Associated with Metabolic Syndrome in Morbidly Obese Patients

Authors: Esther Torrecilla, Gumersindo Fernández-Vázquez, David Vicent, Franco Sánchez-Franco, Ana Barabash, Lucio Cabrerizo, Andrés Sánchez-Pernaute, Antonio J. Torres, Miguel Ángel Rubio

Published in: Obesity Surgery | Issue 3/2012

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Abstract

Background

Hepatic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which converts cortisone (inactive) to cortisol, is downregulated in obesity. However, this compensation fails in obese with metabolic abnormalities, such as diabetes. To further characterize the tissue-specific cortisol regeneration in obesity, we have investigated the mRNA expression of genes related to local cortisol production, i.e., 11β-HSD1, hexose-6-phosphate dehydrogenase (H6PDH) and cortisol action, glucocorticoid receptor (GR) and a cortisol target gene, phosphoenolpyruvate carboxykinase (PEPCK) in the liver, and visceral (VAT) and subcutaneous (SAT) adipose tissues from morbidly obese patients with and without metabolic syndrome (MS).

Methods

Fifty morbidly obese patients undergoing bariatric surgery, 14 men (mean age, 41.3 ± 3.5 years; BMI, 48.0 ± 3.6 kg/m2) and 36 women (mean age, 44.6 ± 1.9 years; BMI, 44.9 ± 1.2 kg/m2), were classified as having MS (MS+, n = 20) or not (MS−, n = 30). Tissue mRNA levels were measured by real-time polymerase chain reaction.

Results

Hepatic mRNA levels of these genes were higher in obese patients with MS (11β-HSD1, P = 0.002; H6PDH, P = 0.043; GR, P = 0.033; PEPCK, P = 0.032) and positively correlated with the number of clinical characteristics that define the MS. The expression of the four genes positively correlated among them. In contrast to the liver, these genes were not differently expressed in VAT or SAT, when MS+ and MS− obese patients were compared.

Conclusions

Coordinated liver-specific upregulation of genes involved in local cortisol regeneration and action support the concept that local hepatic hypercortisolism contributes to development of MS in morbidly obese patients.
Literature
1.
Anagnostis P, Athyros VG, Tziomalos K, et al. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab. 2009;94:2692–701.PubMedCrossRef
2.
Cooper MS, Stewart PM. 11Beta-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin Endocrinol Metab. 2009;94:4645–54.PubMedCrossRef
3.
Tomlinson JW, Walker EA, Bujalska IJ, et al. 11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev. 2004;25:831–66.PubMedCrossRef
4.
Atanasov AG, Nashev LG, Schweizer RA, et al. Hexose-6-phosphate dehydrogenase determines the reaction direction of 11beta-hydroxysteroid dehydrogenase type 1 as an oxoreductase. FEBS Lett. 2004;571:129–33.PubMedCrossRef
5.
Lavery GG, Walker EA, Draper N, et al. Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem. 2006;281:6546–51.PubMedCrossRef
6.
Kotelevtsev Y, Holmes MC, Burchell A, et al. 11Beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A. 1997;94:14924–29.PubMedCrossRef
7.
Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294:2166–70.PubMedCrossRef
8.
Paterson JM, Morton NM, Fievet C, et al. Metabolic syndrome without obesity: hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci U S A. 2004;101:7088–93.PubMedCrossRef
9.
Palermo M, Shackleton CH, Mantero F, et al. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol (Oxf). 1996;45:605–11.CrossRef
10.
Stewart PM, Wallace AM, Atherden SM, et al. Mineralocorticoid activity of carbenoxolone: contrasting effects of carbenoxolone and liquorice on 11 beta-hydroxysteroid dehydrogenase activity in man. Clin Sci (Lond). 1990;78:49–54.
11.
Stewart PM, Boulton A, Kumar S, et al. Cortisol metabolism in human obesity: impaired cortisone → cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab. 1999;84:1022–7.PubMedCrossRef
12.
Rask E, Olsson T, Soderberg S, et al. Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab. 2001;86:1418–21.PubMedCrossRef
13.
Rask E, Walker BR, Soderberg S, et al. Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab. 2002;87:3330–6.PubMedCrossRef
14.
Valsamakis G, Anwar A, Tomlinson JW, et al. 11Beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004;89:4755–61.PubMedCrossRef
15.
Tomlinson JW, Moore JS, Clark PM, et al. Weight loss increases 11beta-hydroxysteroid dehydrogenase type 1 expression in human adipose tissue. J Clin Endocrinol Metab. 2004;89:2711–6.PubMedCrossRef
16.
Westerbacka J, Yki-Jarvinen H, Vehkavaara S, et al. Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab. 2003;88:4924–31.PubMedCrossRef
17.
Sandeep TC, Andrew R, Homer NZ, et al. Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11beta-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes. 2005;54:872–9.PubMedCrossRef
18.
Desbriere R, Vuaroqueaux V, Achard V, et al. 11Beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients. Obesity (Silver Spring). 2006;14:794–8.CrossRef
19.
Mariniello B, Ronconi V, Rilli S, et al. Adipose tissue 11beta-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing’s syndrome. Eur J Endocrinol. 2006;155:435–41.PubMedCrossRef
20.
Veilleux A, Rheaume C, Daris M, et al. Omental adipose tissue type 1 11 beta-hydroxysteroid dehydrogenase oxoreductase activity, body fat distribution, and metabolic alterations in women. J Clin Endocrinol Metab. 2009;94:3550–7.PubMedCrossRef
21.
Tomlinson JW, Sinha B, Bujalska I, et al. Expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity. J Clin Endocrinol Metab. 2002;87:5630–5.PubMedCrossRef
22.
Paulmyer-Lacroix O, Boullu S, Oliver C, et al. Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab. 2002;87:2701–5.PubMedCrossRef
23.
Kannisto K, Pietilainen KH, Ehrenborg E, et al. Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab. 2004;89:4414–21.PubMedCrossRef
24.
Engeli S, Bohnke J, Feldpausch M, et al. Regulation of 11beta-HSD genes in human adipose tissue: influence of central obesity and weight loss. Obes Res. 2004;12:9–17.PubMedCrossRef
25.
Lindsay RS, Wake DJ, Nair S, et al. Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians. J Clin Endocrinol Metab. 2003;88:2738–44.PubMedCrossRef
26.
Uckaya G, Karadurmus N, Kutlu O, et al. Adipose tissue 11-beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase gene expressions are increased in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract. 2008;82 Suppl 2:S135–40.PubMedCrossRef
27.
Koska J, de Courten B, Wake DJ, et al. 11Beta-hydroxysteroid dehydrogenase type 1 in adipose tissue and prospective changes in body weight and insulin resistance. Obesity (Silver Spring). 2006;14:1515–22.CrossRef
28.
Tomlinson JW, Finney J, Gay C, et al. Impaired glucose tolerance and insulin resistance are associated with increased adipose 11beta-hydroxysteroid dehydrogenase type 1 expression and elevated hepatic 5alpha-reductase activity. Diabetes. 2008;57:2652–60.PubMedCrossRef
29.
Muñoz R, Carvajal C, Escalona A, et al. 11Beta-hydroxysteroid dehydrogenase type 1 is overexpressed in subcutaneous adipose tissue of morbidly obese patients. Obes Surg. 2009;19:764–70.PubMedCrossRef
30.
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation. 2005;112:2735–52.PubMedCrossRef
31.
Iwasaki Y, Takayasu S, Nishiyama M, et al. Is the metabolic syndrome an intracellular Cushing state? Effects of multiple humoral factors on the transcriptional activity of the hepatic glucocorticoid-activating enzyme (11beta-hydroxysteroid dehydrogenase type 1) gene. Mol Cell Endocrinol. 2008;285:10–8.PubMedCrossRef
32.
Liu Y, Nakagawa Y, Wang Y, et al. Increased glucocorticoid receptor and 11{beta}-hydroxysteroid dehydrogenase type 1 expression in hepatocytes may contribute to the phenotype of type 2 diabetes in db/db mice. Diabetes. 2005;54:32–40.PubMedCrossRef
33.
Morton NM, Densmore V, Wamil M, et al. A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action. Diabetes. 2005;54:3371–8.PubMedCrossRef
34.
Livingstone DE, Jones GC, Smith K, et al. Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese zucker rats. Endocrinology. 2000;141:560–3.PubMedCrossRef
35.
Baudrand R, Carvajal CA, Riquelme A. Overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in hepatic and visceral adipose tissue is associated with metabolic disorders in morbidly obese patients. Obes Surg. 2010;20:77–83.PubMedCrossRef
36.
Simonyte K, Rask E, Naslund I, et al. Obesity is accompanied by disturbances in peripheral glucocorticoid metabolism and changes in FA recycling. Obesity (Silver Spring). 2009;17:1982–7.CrossRef
37.
Wang Y, Nakagawa Y, Liu L, et al. Tissue-specific dysregulation of hexose-6-phosphate dehydrogenase and glucose-6-phosphate transporter production in db/db mice as a model of type 2 diabetes. Diabetologia. 2011;54:440–50.PubMedCrossRef
38.
Yabaluri N, Bashyam MD. Hormonal regulation of gluconeogenic gene transcription in the liver. J Biosci. 2010;35:473–84.PubMedCrossRef
39.
Alberts P, Engblom L, Edling N, et al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002;45:1528–32.PubMedCrossRef
40.
Bhat BG, Younis H, Herrera J, et al. Antisense inhibition of 11bhydroxysteroid dehydrogenase type 1 improves diabetes in a novel cortisone-induced diabetic KK mouse model. Biochem Biophys Res Com. 2008;365:740–5.PubMedCrossRef
41.
Edgerton DS, Basu R, Ramnanan CJ, et al. Effect of 11b-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. Am J Physiol Endocrinol Metab. 2010;298:E1019–26.PubMedCrossRef
42.
Balkau B, Valensi P, Eschwege E, et al. A review of the metabolic syndrome. Diabetes Metab. 2007;3:405–13.CrossRef
43.
Rosenstock J, Banarer S, Fonseca VA, et al. The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy. Diabetes Care. 2010;33:1516–22.PubMedCrossRef
44.
Morton NM. Obesity and corticosteroids: 11b-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010;316:154–64.PubMedCrossRef
Metadata
Title
Liver Upregulation of Genes Involved in Cortisol Production and Action Is Associated with Metabolic Syndrome in Morbidly Obese Patients
Authors
Esther Torrecilla
Gumersindo Fernández-Vázquez
David Vicent
Franco Sánchez-Franco
Ana Barabash
Lucio Cabrerizo
Andrés Sánchez-Pernaute
Antonio J. Torres
Miguel Ángel Rubio
Publication date
01-03-2012
Publisher
Springer-Verlag
Published in
Obesity Surgery / Issue 3/2012
Print ISSN: 0960-8923
Electronic ISSN: 1708-0428
DOI
https://doi.org/10.1007/s11695-011-0524-9

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