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Novel Adipose Tissue–Mediated Resistance to Diet-Induced Visceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1–Deficient Mice
Open accessAbstract
The metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes, and dyslipidemia) resembles Cushing’s Syndrome, but without elevated circulating glucocorticoid levels. An emerging concept suggests that the aberrantly elevated levels of the intracellular glucocorticoid reamplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and “Cushingoid” obesity. Transgenic overexpression of 11β-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11β-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11β-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11β-HSD-1 nullizygous (11β-HSD-1−/−) mice. 11β-HSD-1−/− mice expressed lower resistin and tumor necrosis factor-α, but higher peroxisome proliferator–activated receptor-γ, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11β-HSD-1−/− adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11β-HSD-1−/− mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat–fed 11β-HSD-1−/− mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories. These data provide the first in vivo evidence that adipose 11β-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11β-HSD-1 deficiency or inhibition.
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“These include increased production of inflammatory cytokines, 35,36 plasminogen activator inhibitor-1, 37 and other bioactive products 38 -40 ; at the same time the potentially protective adipokine, adiponectin, is reduced.41,42”
From Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (2005) · cites this paper as [38]
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Andrew, R., Westerbacka, J., Wahren, J., Yki‐Järvinen, H., & Walker, B. R. (2005) · Diabetes · doi:10.2337/diabetes.54.5.1364 · Cited by 98
“Ra extra Ra d4-cortisolss AUC E (Ra d4-cortisolss) (Ra cortisolss) (7) Estimating extrahepatic (visceral) versus hepatic contribution to splanchnic cortisol generation.”
BackgroundSelf-citationAdipocytes, aldosterone and obesity-related hypertension
Cat, A. N. D., Friederich‐Persson, M., White, A. D., & Touyz, R. M. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0025 · Cited by 94
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Michailidou, Z., Turban, S., Miller, E., Zou, X., Schrader, J., Ratcliffe, P. J., Hadoke, P. W. F., Walker, B. R., Iredale, J. P., Morton, N. M., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.259325 · Cited by 93
Self-citationWhat are subcutaneous adipocytes really good for…?
Paus, R., Klein, J. C., Permana, P. A., Owecki, M., Chaldakov, G. N., Böhm, M., Hausman, G., Lapiere, C. M., Atanassova, P. K., Sowiński, J., et al. (2006) · Experimental Dermatology · doi:10.1111/j.1600-0625.2006.00519_1.x · Cited by 101
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“Abnormal downregulation of adiponectin and UCP2 gene expression has been reported in adipose tissue from first-degree relatives of type 2 diabetic patients (45,46), whereas insulin sensitization in 11 -hydroxysteroid dehydrogenase type 1–deficient mice or in Crebbp heterozygous mice is associated with parallel inducti…”
BackgroundImpact of Glucocorticoid Excess on Glucose Tolerance: Clinical and Preclinical Evidence
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“Adipose-specific 11β-HSD1 over-expression in mice (in subcutaneous and epididymal depots) results in obesity and IR in mice [85], whereas inhibiting 11β-HSD1 enhanced adipose insulin sensitivity [86].”
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“Conversely, global 11 HSD1 knockout mice are protected from the metabolic consequences of dietary obesity, at least in part, through adipose tissue insulin sensitization and fat redistribution away from the visceral depot (16,17).”
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“Thus, supplementation therapy may help to treat the progressive decline of circulating DHEA levels with aging and may prevent elevated intra-adipose cortisol levels (or corticosterone in rodents), which antagonize the effects of insulin and induce hypertrophy and visceral fat accumulation (30, 35).”
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InfluentialThe role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response
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“They show increased insuli sensitivity and are protected against metabolic disease (Morton et al., 2001; Morton et al., 2004), show increased angiogenesis following injury (Small et al., 2005) and resist cognitive decline in old age (Yau et al., 2007; Yau et al., 2001).”
BackgroundSelf-citationNovel targets for potential therapeutic use in Diabetes mellitus
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A novel selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis
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“Conversely, global deletion of 11b-HSD1 caused reduced visceral fat accumulation and improved insulin sensitivity on a high fat diet (Kotelevtsev et al. 1997, Morton et al. 2004).”
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11β-HSD1 Inhibitors for the Treatment of Type 2 Diabetes and Cardiovascular Disease
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“It has been suggested that interindividual variation in the ability of humans to regulate adipose 11 -HSD-1 in response to a diet high in saturated fat (Western diet) may play a role in determining their overall susceptibility to insulin resistance and type 2 diabetes (10).”
BackgroundDepot‐specific steroidogenic gene transcription in human adipose tissue
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Targeting the pre-receptor metabolism of cortisol as a novel therapy in obesity and diabetes
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Mineralocorticoid receptors in the metabolic syndrome
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“Like 11 -HSD1-deficient mice (57, 58), C/EBP / mice are insulin sensitized (59) and resist the adverse metabolic effects of a high-fat diet (60, 61).”
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Metadata
- Authors
- Morton, N. M., Paterson, J. M., Masuzaki, H., Holmes, M. C., Staels, B., Fievet, C., Walker, B. R., Flier, J. S., Mullins, J. J., & Seckl, J. R.
- Affiliations
- Western General Hospital (GB)
- University of Edinburgh (GB)
- Kyoto University (JP)
- Inserm (FR)
- Département d’ Athérosclérose,U.545 INSERM, Institut Pasteur de Lille, Lille, France
- Beth Israel Deaconess Medical Center (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2004-04-01
- Volume
- 53
- Issue
- 4
- Pages
- 931-938
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2154972651
- Cited by
- 512
- References
- 49
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 9 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 5 · 2019: 10 · 2018: 10 · 2017: 12 · 2016: 21 · 2015: 19 · 2014: 24 · 2013: 35 · 2012: 37
- FWCI
- 32.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (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 › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- 11β-hydroxysteroid dehydrogenase type 1, visceral obesity, adipose tissue, metabolic syndrome, insulin resistance, resistin, TNF-α, PPARγ, adiponectin, UCP2, insulin-stimulated glucose uptake, high-fat diet, body fat distribution, type 2 diabetes
- MeSH terms
- Uncoupling Protein 2, Adipose Tissue, Animals, Blood Glucose, Body Temperature, Body Weight, Cholesterol, Diet, Gene Expression Regulation, Glucose Tolerance Test, Insulin, Ion Channels, Male, Obesity, Transcription Factors, Triglycerides, Adipocytes, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Mitochondrial Proteins, Membrane Transport Proteins, 11-beta-Hydroxysteroid Dehydrogenase Type 1, Mice
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