Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice.
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.
Morton
Nicholas M
NM
Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK. nik.morton@ed.ac.uk
Paterson
Janice M
JM
Masuzaki
Hiroaki
H
Holmes
Megan C
MC
Staels
Bart
B
Fievet
Catherine
C
Walker
Brian R
BR
Flier
Jeffrey S
JS
Mullins
John J
JJ
Seckl
Jonathan R
JR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001831:Body Temperature; D001835:Body Weight; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007328:Insulin / Q000494:pharmacology; D007473:Ion Channels; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000517:prevention & control*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D000071246:Uncoupling Protein 2
D001786:Blood Glucose; D007328:Insulin; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D002784:Cholesterol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1