Cited by 239Adipokines, Inflammation, and Metabolic DiseasesHormonal Regulation and HypertensionAdrenal Hormones and Disorders

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Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue

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Seckl, J. R.·2004·Recent Progress in Hormone Research

DOI 10.1210/rp.59.1.359

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Abstract

The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.

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Background
Adipose tissue 11β-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing’s syndrome
Mariniello, B., Ronconi, V., Rilli, S., Bernante, P., Boscaro, M., Mantero, F., & Giacchetti, G. (2006) · European Journal of Endocrinology · doi:10.1530/eje.1.02228 · Cited by 77
“Intracellular glucocorticoid metabolism is regulated at a prereceptor level (1) by the activity of two isoforms of the 11b-hydrxysteroid dehydrogenase enzyme: 11b-Hydrxysteroid dehydrogenase type 1 (11b-HSD1) is a microsomal enzyme, which acts mainly as a NADP(H)dependent reductase converting inactive cortisone (E) to…”
Background
Genetics of metabolic syndrome
JOY, T. R., Lahiry, P., Pollex, R. L., & Hegele, R. A. (2008) · Current Diabetes Reports · doi:10.1007/s11892-008-0025-y · Cited by 75
“Unfortunately, HSD11B1 SNPs are not consistently associated with MetS, despite overexpression producing a classic MetS phenotype in mice [47, 48 ].”
Background
11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents
Boyle, C. D., & Kowalski, T. J. (2009) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543770902967658 · Cited by 74
“Two 11β-HSD isozymes have been identified, 11β-HSD1 and 11β-HSD2 [26,27].”
Natural Mixtures of Persistent Organic Pollutants (POP) Increase Weight Gain, Advance Puberty, and Induce Changes in Gene Expression Associated with Steroid Hormones and Obesity in Female Zebrafish
Lyche, J. L., Nourizadeh-Lillabadi, R., Almaas, C., Stavik, B., Berg, V., Skåre, J. U., Aleström, P., & Ropstad, E. (2010) · Journal of Toxicology and Environmental Health · doi:10.1080/15287394.2010.481618 · Cited by 74
“In addition to regulation of fatty acids homeostasis, glucocorticoids induce obesity by central stimulation of appetite (Seckl et al., 2004).”
Background
Updated survey of the steroid-converting enzymes in human adipose tissues
Tchernof, A., Mansour, M. F., Pelletier, M., Boulet, M.-M., Nadeau, M., & Luu-The, V. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.11.011 · Cited by 73
“have shown that peripheral conversion of glucocorticoids is altered [23,24], that adipose tissue cortisol has a slow turnover, and that it”
Diabetes Mellitus Secondary to Endocrine Diseases: An Update of Diagnostic and Treatment Particularities
Popoviciu, M. S., Păduraru, L., Nutas, R. M., Ujoc, A. M., Yahya, G., Metwally, K. A., & Cavalu, S. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612676 · Cited by 93
Endocrinopathic laminitis in the horse
Johnson, P. J., Messer, N. T., Slight, S. H., Wiedmeyer, C. E., Buff, P. R., & Ganjam, V. K. (2004) · Clinical techniques in equine practice · doi:10.1053/j.ctep.2004.07.004 · Cited by 71
Fetal and Neonatal Pathways to Obesity
Gluckman, P. D., Hanson, M. A., Beedle, A. S., & Raubenheimer, D. (2008) · Frontiers of hormone research · doi:10.1159/000115337 · Cited by 71
Overexpression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Hepatic and Visceral Adipose Tissue is Associated with Metabolic Disorders in Morbidly Obese Patients
Baudrand, R. F., Carvajal, C. A., Riquelme, A. J., Morales, M., Solı́s, N., Pizarro, M., Escalona, A., Boza, C., Pérez, G., Domínguez, A., et al. (2009) · Obesity Surgery · doi:10.1007/s11695-009-9937-0 · Cited by 68
“We also observed a trend to a higher hepatic 11β-HSD1 expression in those patients who had diagnosis of hypertension, which could be explained by higher angiotensinogen production secondary to hepatic hypercortisolism, as was observed in the transgenic mice model with selective overexpression of 11β-HSD1 in liver [17,…”
Background
Glucocorticoid metabolism within superficial subcutaneous rather than visceral adipose tissue is associated with features of the metabolic syndrome in South African women
Goedecke, J. H., Wake, D. J., Levitt, N. S., Lambert, E. V., Collins, M. R., Morton, N. M., Andrew, R., Seckl, J. R., & Walker, B. R. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02552.x · Cited by 67
Self-citation
Benzothiazole derivatives as novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1
Su, X., Vicker, N., Ganeshapillai, D., Smith, A., Purohit, A., Reed, M. J., & Potter, B. V. L. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.10.022 · Cited by 66
Arginine vasopressin: Direct and indirect action on metabolism
Yoshimura, M., Conway-Campbell, B. L., & Ueta, Y. (2021) · Peptides · doi:10.1016/j.peptides.2021.170555 · Cited by 75
Dose dependent development of diabetes mellitus and non-alcoholic steatohepatitis in monosodium glutamate-induced obese mice
Sasaki, Y., Suzuki, W., Shimada, T., Iizuka, S., Nakamura, S., Nagata, M., Fujimoto, M., Tsuneyama, K., HOKAO, R., Miyamoto, K., et al. (2009) · Life Sciences · doi:10.1016/j.lfs.2009.07.017 · Cited by 64
Expression of genes related to glucocorticoid action in human subcutaneous and omental adipose tissue
Veilleux, A., Laberge, P. Y., Morency, J., Noël, S., Luu-The, V., & Tchernof, A. (2010) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2010.02.024 · Cited by 64
High-fructose diet leads to visceral adiposity and hypothalamic leptin resistance in male rats — do glucocorticoids play a role?
Bursać, B. N., Teofilović, A., Nestorović, N. M., Veličković, N. A., Milutinović, D. V., Matić, G. M., & Djordjevic, A. D. (2014) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2013.12.005 · Cited by 70
Glycyrrhetinic acid, the active principle of licorice, can reduce the thickness of subcutaneous thigh fat through topical application
Armanini, D., Nacamulli, D., Francini‐Pesenti, F., Battagin, G., Ragazzi, E., & Fiore, C. (2005) · Steroids · doi:10.1016/j.steroids.2005.01.007 · Cited by 60
Voluntary wheel running initially increases adrenal sensitivity to adrenocorticotrophic hormone, which is attenuated with long-term training
Campbell, J. E., Rakhshani, N., Fediuc, S., Bruni, S. G., & Riddell, M. C. (2008) · Journal of Applied Physiology · doi:10.1152/japplphysiol.91128.2008 · Cited by 60
“It has been well established that chronically elevated levels of plasma GCs can lead to the development of a number of harmful pathologies, including impaired insulin signaling, central adiposity, skeletal muscle atrophy, immune suppression, and type 2 diabetes mellitus (6, 16, 24, 33).”
Background
Cortisol: the villain in Metabolic Syndrome?
Paredes, S., & Ribeiro, L. V. P. T. (2014) · Revista da Associação Médica Brasileira · doi:10.1590/1806-9282.60.01.017 · Cited by 61
Anthrax lethal factor represses glucocorticoid and progesterone receptor activity
Webster, J. I., Tonelli, L. H., Moayeri, M., Simons, S. S., Leppla, S. H., & STERNBERG, E. M. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1036973100 · Cited by 60
“Furthermore, dysregulation of this enzyme has been correlated with obesity and type 2 diabetes (Rask et al., 2001; Lindsay et al., 2003; Westerbacka et al., 2003; Seckl et al., 2004; Valsamakis et al., 2004) and decreased 11β-HSD mRNA is seen in ulcerative colitis (Takahasi et al.”
Background
11β-Hydroxysteroid dehydrogenases in human endometrium
McDonald, S. E., Henderson, T. A., Gómez-Sánchez, C. E., Critchley, H., & Mason, J. I. (2006) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.12.010 · Cited by 57
The metabolic syndrome and schizophrenia: A review
Meyer, J. M., Koro, C. E., & L'Italien, G. J. (2005) · International Review of Psychiatry · doi:10.1080/09540260500071798 · Cited by 55
“…that converts inactive circulating 11-keto steroids into active glucocorticoids, are elevated in adipose tissue in some obese individuals, suggesting that adipose tissue-related glucocorticoid excess may underlie the risk for hyperglycemia related to greater IAF mass (Seckl et al., 2004).”
BackgroundInfluential
Growth Hormone (GH) Substitution in GH-Deficient Patients Inhibits 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in Adipose Tissue
Paulsen, S. K., Pedersen, S. B., Jørgensen, J. O. L., Fisker, S., Christiansen, J. S., Flyvbjerg, A., & Richelsen, B. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1694 · Cited by 55
Extra-adrenal regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1: physiological regulator and pharmacological target for energy partitioning
Walker, B. R. (2007) · Proceedings of The Nutrition Society · doi:10.1017/s002966510700523x · Cited by 52
“The influence of 11b-HSD1 in mice and its potential as a therapeutic target in human subjects has been extensively reviewed elsewhere (Seckl & Walker, 2001, 2004; Seckl et al. 2004; Tomlinson et al. 2004b).”
Background
Stress, stress reduction and obesity in childhood and adolescence
Kappes, C., Stein, R., Körner, A., Merkenschlager, A., & Kiess, W. (2023) · Hormone Research in Paediatrics · doi:10.1159/000519284 · Cited by 51
“Those conversions occur in different tissues including kidney, liver and adipose tissue [58].”
Background
Visceral Fat Accumulation and Postdexamethasone Serum Cortisol Levels in Patients With Adrenal Incidentaloma
Debono, M., Prema, A., Hughes, T., Bull, M., Ross, R. J. M., & Newell-Price, J. D. C. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4276 · Cited by 53
Tumor necrosis factor-α upregulates 11β-hydroxysteroid dehydrogenase type 1 expression by CCAAT/enhancer binding protein-β in HepG2 cells
Ignatova, I. D., Kostadinova, R. M., Goldring, C. E., Nawrocki, A. R., Frey, F. J., & Frey, B. M. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90531.2008 · Cited by 53
The multifaceted mineralocorticoid receptor
Gomez‐Sanchez, E., & Gomez‐Sanchez, C. E. (2014) · Comprehensive Physiology · doi:10.1002/j.2040-4603.2014.tb00569.x · Cited by 55
“…cortisone and 11-dehydrocorticosterone, it has recently become a target for the development of speciﬁc treatments of the metabolic syndrome, type II diabetes, obesity, and the dementia associated with aging in which excessive cortisol action has a role (15, 20, 105, 221, 321, 408, 441, 465).”
The native anti-glucocorticoid paradigm
Muller, C., Hennebert, O., & Morfin, R. F. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.03.001 · Cited by 53
Sex‐ and age‐specific effects of nutrition in early gestation and early postnatal life on hypothalamo‐pituitary‐adrenal axis and sympathoadrenal function in adult sheep
Poore, K. R., Boullin, J. P., Cleal, J. K., Newman, J. P., Noakes, D. E., Hanson, M. A., & Green, L. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.187682 · Cited by 51
Actions of PPARγ agonism on adipose tissue remodeling, insulin sensitivity, and lipemia in absence of glucocorticoids
Berthiaume, M., Sell, H., Lalonde, J., Gélinas, Y., Tchernof, A., Richard, D., & Deshaies, Y. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00339.2004 · Cited by 51
The Adrenal Cortex and its Disorders
Miller, W. L. (2009) · Wiley eBooks · doi:10.1002/9781444316728.ch13 · Cited by 51
Emodin, an 11β-hydroxysteroid dehydrogenase type 1 inhibitor, regulates adipocyte function in vitro and exerts anti-diabetic effect in ob/ob mice
Wang, Y.-J., Huang, S., Feng, Y., Ning, M., & Leng, Y. (2012) · Acta Pharmacologica Sinica · doi:10.1038/aps.2012.87 · Cited by 50
Regulation of Steroidogenesis
Bremer, A. A., & Miller, W. L. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-408134-5.00013-5 · Cited by 54
Nutritional aspects modulating brain development and the responses to stress in early neonatal life
Walker, C. (2005) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2005.08.010 · Cited by 47
Endurance exercise training increases adipose tissue glucocorticoid exposure: adaptations that facilitate lipolysis
Campbell, J. E., Fediuc, S., Hawke, T. J., & Riddell, M. C. (2009) · Metabolism · doi:10.1016/j.metabol.2009.01.002 · Cited by 49
“It is important to note that the adipogenic effects of GCs are often seen in situations where insulin is also elevated [3,15,27], rather than in humans on dietary restriction [8] or in animal models exposed to exercise training, as is shown here (Table 2) and in our previous study [16].”
Result
Fructose consumption enhances glucocorticoid action in rat visceral adipose tissue
Bursać, B. N., Djordjevic, A. D., Teofilović, A., Milutinović, D. V., Veličković, N. A., Nestorović, N. M., & Matić, G. M. (2012) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2012.09.002 · Cited by 47
Modern management of mild autonomous cortisol secretion
Delivanis, D. A., Athimulam, S., & Bancos, I. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1551 · Cited by 46
“Increased local cortisol synthesis in adipose tissue via conversion of inactive cortisone to active cortisol by the action of type 1, 11beta-hydroxysteroid dehydrogenase enzyme, is another well-recognized etiologic factor for abdominal obesity.(77,79) Chronic excess of glucocorticoids, such as that seen with overt CS,…”
Background
Adrenal cortex and its disorders
Miller, W. L., & Flück, C. E. (2014) · Elsevier eBooks · doi:10.1016/b978-1-4557-4858-7.00022-6 · Cited by 45
Developmental regulation of the lung in preparation for life after birth: hormonal and nutritional manipulation of local glucocorticoid action and uncoupling protein–2
Gnanalingham, M. G., Mostyn, A., Gardner, D. S., Stephenson, T. J., & Symonds, M. E. (2006) · Journal of Endocrinology · doi:10.1677/joe.1.06530 · Cited by 43
Fetal endocrine therapy for congenital adrenal hyperplasia should not be done
Miller, W. L. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.01.005 · Cited by 40
Effects of antisense-mediated inhibition of 11β-hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism
Li, G., Hernández‐Ono, A., Crooke, R. M., Graham, M. J., & Ginsberg, H. N. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m013748 · Cited by 41
Coffee inhibits the reactivation of glucocorticoids by 11β‐hydroxysteroid dehydrogenase type 1: A glucocorticoid connection in the anti‐diabetic action of coffee?
Atanasov, A. G., Dzyakanchuk, A. A., Schweizer, R. A. S., Nashev, L. G., Maurer, E. M., & Odermatt, A. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.06.046 · Cited by 41
“glucocorticoid production as a result of adrenal tumors or because of prolonged treatment with high pharmacologic doses [31].”
Background
The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11β-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue
Marcolongo, P., Piccirella, S., Senesi, S., Wunderlich, L., Gerin, I., Mandl, J., Fulceri, R., Bánhegyi, G., & Benedetti, A. (2007) · Endocrinology · doi:10.1210/en.2006-1472 · Cited by 39
Adrenocortical tumors and insulin resistance: What is the first step?
Altieri, B., Tirabassi, G., Casa, S. D., Ronchi, C. L., Balercia, G., Orio, F., Pontecorvi, A., Colao, A., & Muscogiuri, G. (2015) · International Journal of Cancer · doi:10.1002/ijc.29950 · Cited by 39

Authors: Seckl, J. R.
Affiliations: Western General Hospital (GB)
Corresponding author: Seckl, J. R.
ORCID: Seckl, J. R.
Venue: Recent Progress in Hormone Research
Publisher: The Endocrine Society
Published: 2004-01-01
Volume: 59
Issue: 1
Pages: 359-393
ISSN: 0079-9963 (ISSN-L)
DOI: 10.1210/rp.59.1.359
OpenAlex: W2129008449
Semantic Scholar: 4c2b062bc15435b616374945d43d7e9a6e33c792
Cited by: 239
References: 147
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 5 · 2016: 1 · 2015: 9 · 2014: 11 · 2013: 15 · 2012: 18
FWCI: 3.34
Type: journal article
Language: en
Open access: diamond
doi.org
Locations: Recent Progress in Hormone Research (publishedVersion)
PubMed (publishedVersion)
Funders: Wellcome Trust
British Heart Foundation
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords: 11β-hydroxysteroid dehydrogenase type 1, adipose tissue, glucocorticoids, metabolic syndrome, obesity, insulin resistance, type 2 diabetes, 11-keto steroids, transgenic mice, high-fat feeding, therapeutic target
MeSH terms: Adipose Tissue, Adrenal Glands, Animals, Glucocorticoids, Humans, Hypothalamus, Liver, Mice, Transgenic, Obesity, Pituitary Gland, Mice, Knockout, Metabolic Syndrome, 11-beta-Hydroxysteroid Dehydrogenases, Mice

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Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue

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