Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice

N M Morton, J M Paterson, H Masuzaki, M C Holmes, B Staels, C Fievet, B R Walker, J S Flier, J J Mullins, J R Seckl

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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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11beta-HSD-1 nullizygous (11beta-HSD-1(-/-)) mice. 11beta-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 11beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11beta-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 11beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11beta-HSD-1 deficiency or inhibition.

Original languageEnglish
Pages (from-to)931-938
Number of pages8
Issue number4
Publication statusPublished - Apr 2004

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