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- Title
Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice.
- Authors
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.
- 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 11βHSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11β-HSD-1 nullizygous (11βHSD-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-fatfed 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.
- Subjects
OBESITY; TYPE 2 diabetes; DIABETES complications; INSULIN resistance; CUSHING'S syndrome; ENDOCRINE diseases
- Publication
Diabetes, 2004, Vol 53, Issue 4, p931
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.4.931