Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity.
Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11beta-hydroxysteroid dehydrogenases (11betaHSDs). 11betaHSD1 activates GCs, while 11betaHSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11betaHSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocyte-specific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11betaHSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11betaHSD2). Transgenic mice have increased 11betaHSD2 expression and activity exclusively in adipose tissue, with the highest levels in subcutaneous adipose tissue, while systemic indexes of GC exposure are unchanged. Transgenic mice resist weight gain on high-fat diet due to reduced fat mass accumulation. This improved energy balance is associated with decreased food intake, increased energy expenditure, and improved glucose tolerance and insulin sensitivity. Adipose tissue gene expression in transgenic mice is characterized by decreased expression of leptin and resistin and increased expression of adiponectin, peroxisome proliferator-activated receptor gamma, and uncoupling protein 2. These data suggest that reduction of active GCs exclusively in adipose tissue is an important determinant of a favorable metabolic phenotype with respect to energy homeostasis and the metabolic syndrome.
Kershaw
Erin E
EE
Division of Endocrinology and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ekershaw@bidmc.harvard.edu <ekershaw@bidmc.harvard.edu>
Morton
Nicholas M
NM
Dhillon
Harveen
H
Ramage
Lynne
L
Seckl
Jonathan R
JR
Flier
Jeffrey S
JS
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000201:enzymology / Q000502:physiology*; D000273:Adipose Tissue; D000375:Aging; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D004041:Dietary Fats; D050556:Fatty Acid-Binding Proteins; D015870:Gene Expression; D005938:Glucocorticoids / Q000502:physiology*; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000201:enzymology / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000201:enzymology / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D015430:Weight Gain
D002352:Carrier Proteins; D004041:Dietary Fats; D050556:Fatty Acid-Binding Proteins; D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2