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

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

• Authors: Nicholas M Morton, Janice M Paterson, Hiroaki Masuzaki, Megan C Holmes, Bart Staels, Catherine Fievet, Brian R Walker, Jeffrey S Flier, John J Mullins, Jonathan R Seckl
• Journal: Diabetes (Diabetes) Vol. 53 Issue 4 Pg. 931-8 (Apr 2004) ISSN: 0012-1797 [Print] United States
• PMID: 15047607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Ion Channels
• Membrane Transport Proteins
• Mitochondrial Proteins
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• Triglycerides
• UCP2 protein, human
• Ucp2 protein, mouse
• Uncoupling Protein 2
• Cholesterol
• 11-beta-Hydroxysteroid Dehydrogenase Type 1

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 1 (deficiency, genetics, physiology)
• Adipocytes (drug effects, physiology)
• Adipose Tissue (physiology)
• Animals
• Blood Glucose (drug effects, metabolism)
• Body Temperature
• Body Weight
• Cholesterol (metabolism)
• Diet
• Gene Expression Regulation
• Glucose Tolerance Test
• Insulin (pharmacology)
• Ion Channels
• Male
• Membrane Transport Proteins (genetics)
• Mice
• Mice, Knockout
• Mitochondrial Proteins (genetics)
• Obesity (genetics, prevention & control)
• Receptors, Cytoplasmic and Nuclear (genetics)
• Transcription Factors (genetics)
• Triglycerides (metabolism)
• Uncoupling Protein 2