Cited by 546Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismCardiovascular Disease and Adiposity

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Novel Adipose Tissue–Mediated Resistance to Diet-Induced Visceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1–Deficient Mice

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Morton, Nicholas M., Paterson, Janice M., Masuzaki, Hiroaki, Holmes, Megan C., Staels, Bart, Fievet, Catherine, Walker, Brian R., Flier, Jeffrey S., Mullins, John J., Seckl, Jonathan R.·2004·Diabetes

DOI 10.2337/diabetes.53.4.931

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Abstract

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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Differences in associations between HSD11B1 gene expression and metabolic parameters in subjects with and without impaired glucose homeostasis
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11β-HSD1 Modulates LPS-Induced Innate Immune Responses in Adipocytes by Altering Expression of PTEN
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“One important metabolic change by 11b-HSD1 inhibition is the reduction in body weight gain and adiposity [Morton et al., 2004; Hermanowski-Vosatka et al., 2005].”
BackgroundInfluential
Topical ER36009, a RARγ-Selective Retinoid, Decreases Abdominal White Adipose Tissue and Elicits Changes in Expression of Genes Related to Adiposity and Thermogenesis
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“11β-HSD1 appears to be important in metabolic disease because higher 11β-HSD1 activity in adipose tissue increases local GC levels and develops metabolic syndrome (metS) [5], whereas lower 11β-HSD1 activity protects against obesity and the metS [6, 7] in mice.”
Background
Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice
Lovdel, A., Suchacki, K. J., Roberts, F. L., Sulston, R. J., Wallace, R. J., Thomas, B. J., Bell, R. M. B., Cervera, I. P., Macpherson, G. J., Morton, N. M., et al. (2024) · Journal of Endocrinology · doi:10.1530/joe-24-0072 · Cited by 7
“Given that Hsd11b1 hypo males have increased core body temperature (Morton et al. 2004), it may be that total Hsd11b1 KO alters the hypothermic effects of CR and thereby influences sex steroid production to compensate for dysregulation of core temperature.”
BackgroundSelf-citation
Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice
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11β-Hydroxysteroid dehydrogenase type 1 as a therapeutic target in the metabolic syndrome
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Background
11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors
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“This is in agreement with previous studies showing Hsd11b1 mice are protected from the accumulation of visceral fat following high-fat diet-feeding (60), and also demonstrate reduced food intake (61).”
Result
Hepatic and visceral adipose tissue 11β HSD 1 expressions are markers of body weight loss after bariatric surgery
Pardina, E., Baena‐Fustegueras, J. A., Fort, J. M., Ferrer, R., Rossell, J., Esteve, M., Peinado‐Onsurbe, J., & Grasa, M. (2015) · Obesity · doi:10.1002/oby.21173 · Cited by 5
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Background
11β-Hydroxysteroid dehydrogenase activity in acromegalic patients with normal or impaired carbohydrate metabolism
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“Conversely, 11b-HSD1 knockout mice are resistant to diet-induced obesity and associated metabolic dysfunction [Kotelevtsev et al., 1997; Morton et al., 2001, 2004], consistent with the idea that excess glucocorticoids are important pathogenic factors of many cardiovascular and metabolic defects…”
Background
High-fat diet-induced increase in glucocorticoids contributes to adipogenesis in obese mice
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“For instance, while acute treatment with GCs can induce lipolysis both in vivo [9 – 11] and in vitro [12 – 14], chronic GC supplement leads to lipid accumulation [15,16], fat deposition [17,18], and obesity [19,20].”
Genetic Variations at the CCAAT/Enhancer-binding Protein δ are Associated with Metabolic Phenotypes in the Japanese Population
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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: Morton, Nicholas M.
Masuzaki, Hiroaki
Holmes, Megan C.
Staels, Bart
Walker, Brian R.
Flier, Jeffrey S.
Mullins, John J.
Seckl, Jonathan R.
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2004-04-01
Volume: 53
Issue: 4
Pages: 931-938
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.53.4.931
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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Novel Adipose Tissue–Mediated Resistance to Diet-Induced Visceral Obesity in 11β-Hydroxysteroid Dehydrogenase Type 1–Deficient Mice

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