A transgenic model of visceral obesity and the metabolic syndrome.
The adverse metabolic consequences of obesity are best predicted by the quantity of visceral fat. Excess glucocorticoids produce visceral obesity and diabetes, but circulating glucocorticoid levels are normal in typical obesity. Glucocorticoids can be produced locally from inactive 11-keto forms through the enzyme 11beta hydroxysteroid dehydrogenase type 1 (11beta HSD-1). We created transgenic mice overexpressing 11beta HSD-1 selectively in adipose tissue to an extent similar to that found in adipose tissue from obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes, hyperlipidemia, and, surprisingly, hyperphagia despite hyperleptinemia. Increased adipocyte 11beta HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.
Masuzaki
H
H
Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA.
Paterson
J
J
Shinyama
H
H
Morton
N M
NM
Mullins
J J
JJ
Seckl
J R
JR
Flier
J S
JS
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000005:Abdomen; D017667:Adipocytes / Q000166:cytology / Q000473:pathology; D000273:Adipose Tissue / Q000201:enzymology* / Q000378:metabolism; D000818:Animals; D001823:Body Composition; D048429:Cell Size; D003345:Corticosterone / Q000097:blood / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D004435:Eating; D018390:Gene Targeting; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology* / Q000235:genetics*; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D014781:Viscera; D015430:Weight Gain
D004041:Dietary Fats; D020738:Leptin; D008055:Lipids; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D008071:Lipoprotein Lipase; D003345:Corticosterone