A Transgenic Model of Visceral Obesity and the Metabolic Syndrome

• Published in: Science (American Association for the Advancement of Science) Vol. 294; no. 5549; pp. 2166 - 2170
• Main Authors: Masuzaki, Hiroaki, Paterson, Janice, Shinyama, Hiroshi, Morton, Nicholas M., Mullins, John J., Seckl, Jonathan R., Flier, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 07.12.2001; American Association for the Advancement of Science; The American Association for the Advancement of Science
• Subjects: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11^b hydroxysteroid dehydrogenase 1; 11b hydroxysteroid dehydrogenase 1; Abdomen; Adipocytes; Adipocytes - cytology; Adipocytes - pathology; Adipose Tissue; Adipose Tissue - enzymology; Adipose Tissue - metabolism; Adipose tissues; administration & dosage; Adrenocortical hormones; Animals; Biological and medical sciences; blood; Body Composition; Body fat; Cell Size; Corticosteroids; Corticosterone; Corticosterone - blood; Corticosterone - metabolism; cytology; Diabetes; Dietary Fats; Dietary Fats - administration & dosage; Disease Models, Animal; Eating; enzymology; Gene Targeting; Genes; Genetically modified mice; genetically modified organisms; genetics; Glucocorticoids; High fat diet; Humans; Hydroxysteroid Dehydrogenases; Hydroxysteroid Dehydrogenases - genetics; Hydroxysteroid Dehydrogenases - metabolism; Hyperglycemia; Hyperglycemia - metabolism; Hyperinsulinism; Hyperinsulinism - metabolism; Insulin Resistance; Leptin; Leptin - metabolism; Lipid Metabolism; Lipids; Lipids - blood; Lipoprotein Lipase; Lipoprotein Lipase - genetics; Lipoprotein Lipase - metabolism; Male; Medical sciences; Messenger RNA; Metabolic diseases; Metabolic disorders; Metabolic Syndrome; Metabolism; Mice; Mice, Transgenic; Obesity; Obesity - enzymology; Obesity - genetics; pathology; Receptors, Glucocorticoid; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Scientific Concepts; Subcutaneous fat; Transgenic animals; Viscera; Visceral fat; Weight Gain; Endocrinopathy; Animal model; Obesity; Adipose tissue; Corticosterone; Rodentia; Nutrition disorder; Transgenic animal; Gene overexpression; Cardiovascular disease; Metabolic diseases; Glucocorticoid; Vertebrata; Concomitant disease; Mammalia; Mouse; X Syndrome; Adrenal hormone; Nutritional status
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1066285

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 11β hydroxysteroid dehydrogenase type 1 (11β HSD-1). We created transgenic mice overexpressing 11β 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 11β HSD-1 activity may be a common molecular etiology for visceral obesity and the metabolic syndrome.