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Diabetes 53:931-938, 2004
© 2004 by the American Diabetes Association, Inc.

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

Nicholas M. Morton1, Janice M. Paterson2, Hiroaki Masuzaki3, Megan C. Holmes4, Bart Staels5,6, Catherine Fievet5,6, Brian R. Walker1, Jeffrey S. Flier7, John J. Mullins2, and Jonathan R. Seckl1

1 Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K
2 Molecular Physiology Laboratory, University of Edinburgh, Edinburgh, U.K
3 Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Kyoto University Graduate School of Medicine, Kyoto, Japan
4 Department of Clinical Neurosciences, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, U.K
5 Département d’ Athérosclérose,U.545 INSERM, Institut Pasteur de Lille, Lille, France
6 Faculté de Pharmacie, Université de Lille II, Lille, France
7 Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Centre and Harvard Medical School, Boston, Massachusetts

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 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11ß-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11ß-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11ß-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11ß-HSD-1 nullizygous (11ß-HSD-1-/-) mice. 11ß-HSD-1-/- mice expressed lower resistin and tumor necrosis factor-{alpha}, but higher peroxisome proliferator–activated receptor-{gamma}, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11ß-HSD-1-/- adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11ß-HSD-1-/- mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat–fed 11ß-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 11ß-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11ß-HSD-1 deficiency or inhibition.

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}ed.ac.uk


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