Adipocyte-Specific Glucocorticoid Inactivation Protects Against Diet-Induced Obesity (original) (raw)

Local glucocorticoid (GC) action depends on intracellular GC metabolism by 11␤-hydroxysteroid dehydrogenases (11␤HSDs). 11␤HSD1 activates GCs, while 11␤HSD2 inactivates GCs. Adipocyte-specific amplification of GCs through transgenic overexpression of 11␤HSD1 produces visceral obesity and the metabolic syndrome in mice. To determine whether adipocytespecific inactivation of GCs protects against this phenotype, we created a transgenic model in which human 11␤HSD2 is expressed under the control of the murine adipocyte fatty acid binding protein (aP2) promoter (aP2-h11␤HSD2). Transgenic mice have increased 11␤HSD2 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 ␥, 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. Diabetes 54:1023-1031, 2005 G lucocorticoids (GCs) play a critical role in multiple metabolic processes, including glucose homeostasis, insulin sensitivity, lipid metabolism, and adipogenesis. GC excess, whether endogenous (Cushing's syndrome) or exogenous, promotes visceral obesity, insulin resistance, dyslipidemia, and hypertension (1). A similar constellation of metabolic abnormalities is associated with idiopathic obesity and defines the much more prevalent metabolic syndrome (1, 2). While subtle alterations in the hypothalamicpituitary-adrenal axis have been reported in idiopathic obesity and the metabolic syndrome, no clear role for increased circulating GCs has been established (3). GC action in target tissues, however, not only depends on circulating GC concentrations and cellular GC receptor (GR) expression but also on tissue-specific intracellular GC metabolism by 11␤-hydroxysteroid dehydrogenases (11␤HSDs) (4). 11␤HSDs act at the prereceptor level to catalyze the interconversion of hormonally active 11␤hydroxylated GCs (cortisol in human and corticosterone in mice) and their hormonally inactive 11␤-keto metabolites (cortisone in humans and 11-dehydrocorticosterone [11DHC] in mice) (5). Two isoforms of 11␤HSD have been identified. 11␤HSD1 is a low-affinity NADPH-dependent reductase expressed primarily in GC target tissues, such as liver, adipose tissue, and the central nervous system, where it amplifies local GC action. 11␤HSD2 is a highaffinity NAD-dependent dehydrogenase expressed primarily in mineralocorticoid target tissues, such as kidney, where it potently decreases local GC action, thus ensuring that only the nonsubstrate aldosterone can access intrinsically nonselective mineralocorticoid receptors (6,7). Evidence is rapidly accumulating to support a role for 11␤HSD1 in the pathogenesis of visceral obesity and the metabolic syndrome. 11␤HSD1 is decreased in liver and enhanced in mesenteric adipose tissue (MAT) in several models of rodent obesity, including leptin-resistant Lepr fa / Lepr fa rats (8,9) and leptin-deficient Lep ob /Lep ob mice (10). Several studies have shown that 11␤HSD1 activity and expression in subcutaneous adipose tissue (SCAT) are positively correlated with obesity and insulin resistance in both men and women (11-17). In addition, polymorphic variability at the 11␤HSD1 locus is associated with increased waist-to-hip ratio in adults (18) and with body composition and insulin resistance in children (19). As such, 11␤HSD1 has been proposed as a novel therapeutic target for the treatment of obesity and the meta-From the