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

  1. Nicholas M. Morton1,
  2. Janice M. Paterson2,
  3. Hiroaki Masuzaki3,
  4. Megan C. Holmes4,
  5. Bart Staels56,
  6. Catherine Fievet56,
  7. Brian R. Walker1,
  8. Jeffrey S. Flier7,
  9. John J. Mullins2 and
  10. Jonathan R. Seckl1
  1. 1Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K
  2. 2Molecular Physiology Laboratory, University of Edinburgh, Edinburgh, U.K
  3. 3Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Kyoto University Graduate School of Medicine, Kyoto, Japan
  4. 4Department of Clinical Neurosciences, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K
  5. 5Département d’ Athérosclérose,U.545 INSERM, Institut Pasteur de Lille, Lille, France
  6. 6Faculté de Pharmacie, Université de Lille II, Lille, France
  7. 7Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, Massachusetts
  1. Address correspondencereprint requests to Nicholas M. Morton, Endocrinology Unit, University of Edinburgh, Molecular Medicine Centre, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, U.K. E-mail: nik.morton{at}


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.


  • B.R.W. has received honoraria for lectures and/or consulting from 3M, Biovitrum, Ipsen, Merck, Novo-Nordisk, Novartis, and Pharmacia. J.R.S. has received honoraria from Unilever. B.R.W. and J.R.S. received a research grant from Biovitrum.

    • Accepted January 16, 2004.
    • Received October 2, 2003.
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