In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11␤-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes. Diabetes 54: [197][198][199][200][201][202][203] 2005 N umerous clinical and biological findings indicate that glucocorticoids are involved in the pathophysiology of abdominal obesity and its accompanying complications. Indeed, an excess of glucocorticoids, when associated with hyperinsulinism, favors an increase of lipogenesis and a decrease of lipolysis, together with a stimulation of hepatic neoglucogenesis and an inhibition of peripheral glucose utilization (1). Alterations in the hypothalamo-pituitary-adrenal (HPA) axis have been described in human obesity and in rodent models of obesity. They could involve a hyperactivity of the central command of ACTH secretion, secondary to an increased exposure or sensitization to stress (2) or decreased negative glucocorticoid feedback (3). In addition, changes in peripheral glucocorticoid signaling with increased visceral adipose tissue glucocorticoid receptor (GR) concentrations and local reactivation of circulating inert cortisone (11-dehydrocorticosterone in rodents) to cortisol (corticosterone) driven by 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) could play a pivotal role (4). However, the origins of the abovementioned dysregulations have not been established.Clinical and experimental evidence shows that the environment during the perinatal period plays an important role in the regulation of both metabolic and hormonal axes in adulthood. In humans, hyperglycemia and hyperinsulinemia in macrosomic fetuses of diabetic mothers were shown to favor later development of overweight (5). Conversely, it has been demonstrated that intrauterine g...

DESBRIERE, RAOUL, VINCENT VUAROQUEAUX, VINCENT ACHARD, SANDRINE BOULLU-CIOCCA, MARTIN LABUHN, ANNE DUTOUR, AND MICHEL GRINO. Increased expression of 11␤-hydroxysteroid dehydrogenase type 1 mRNA in both visceral and subcutaneous adipose tissue of obese patients. Obesity. 2006;14:794 -798. Objective: Data from rodents provide evidence for a causal role of 11␤-hydroxysteroid dehydrogenase type 1 (11␤-HSD-1) in the development of obesity and its complications. In humans, 11␤-HSD-1 is increased in subcutaneous adipose tissue (SAT) of obese patients, and higher adipose 11␤-HSD-1 was associated with features of the metabolic syndrome. To date, there is no evidence for an increased expression of 11␤-HSD-1 in human visceral adipose tissue (VAT), although VAT is the major predictor for insulin resistance and the metabolic syndrome. Research Methods and Procedures: 11␤-HSD-1 and hexose-6-phosphate dehydrogenase (the enzyme responsible for the synthesis of nicotinamide adenine dinucleotide phosphate, the cofactor required for 11␤-HSD-1 oxoreductase activity) mRNA levels were measured using real-time quantitative reverse transcriptase-polymerase chain reaction in abdominal SAT and VAT biopsies obtained from 10 normal-weight and 12 obese women. Adiponectin mRNA was used as an internal control.Results: 11␤-HSD-1 mRNA concentrations were significantly increased in both SAT and VAT of obese patients (720% and 450% of controls, respectively; p Ͻ 0.05) and correlated with hexose-6-phosphate dehydrogenase mRNA levels. The level of VAT 11␤-HSD-1 mRNA correlated with anthropometric parameters: BMI (r ϭ 0.41, p ϭ 0.05), waist circumference (r ϭ 0.44, p ϭ 0.04), abdominal sagittal diameter (r ϭ 0.51, p ϭ 0.02), and percentage fat (r ϭ 0.51, p ϭ 0.02). Discussion: Our results demonstrate for the first time that 11␤-HSD-1 mRNA expression is increased in VAT from obese patients. They strengthen the importance of 11␤-HSD-1 in human obesity and its associated complications and suggest the need of clinical studies with specific 11␤-HSD-1 inhibitors.