Abstract
Glucocorticoids (GCs) are involved in multiple metabolic processes, including the regulation of insulin sensitivity and adipogenesis. Their action partly depends on their intracellular activation by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). We previously demonstrated that central GC administration promotes hyperphagia, body weight gain, hyperinsulinemia and marked insulin resistance at the level of skeletal muscles. Similar dysfunctions have been reported to occur upon specific overexpression of 11β-HSD1 in adipose tissue. The aim of the present study was therefore to determine whether the effects of central GC infusion may enhance local GC activation in white adipose tissue. Male Wistar and Sprague Dawley (SD) rats were intracerebroventricularly infused with GCs for 2 to 3 days. Body weight, food intake and metabolic parameters were measured, and expression of enzymes regulating 11β-HSD1, as well as that of genes regulated by GCs, were quantified. Central GC administration induced a significant increase in body weight gain and in 11β-HSD1 and resistin expression in adipose tissue. A decrease 11β-HSD1 expression was noticed in the liver of SD rats, as a partial compensatory mechanism. Such effects of GCs are centrally elicited. This model of icv dexamethasone infusion thus appears to be a valuable acute model, that helps delineating the initial metabolic defects occurring in obesity. An impaired downregulation of intracellular GC activation in adipose tissue may be important for the development of insulin resistance.
Highlights
Glucocorticoids (GCs) influence a wide variety of physiological functions, including food intake, body weight and energy metabolism [1,2]
We showed that central GC administration induced a significant increase in body weight gain and 11b-HSD1 and resistin expression in adipose tissue, while these changes were not observed when dexamethasone was delivered peripherally
We first tested the effect of intracerebroventricular infusion of dexamethasone in Wistar rats, a strain known for its propensity and homogeneity to develop age-dependent obesity [36]
Summary
Glucocorticoids (GCs) influence a wide variety of physiological functions, including food intake, body weight and energy metabolism [1,2]. A state of hypercorticism is often encountered in idiopathic obesity, circulating cortisol/corticosterone levels can be near normal and even low [7,8]. These observations do not preclude the presence of increased local GC activity in obesity/insulin resistance [9,10]. The physiopathological impact of such an increase has been studied by overexpressing 11b-HSD1 in adipose tissue in mice These rodents have developed a phenotype similar to the metabolic syndrome, with increased central adiposity, impaired glucose tolerance, hypertriglyceridemia but normal circulating corticosterone levels [19,20]. Mice lacking 11b-HSD1 are shown to be resistant to the development of the metabolic syndrome and exhibited improved glucose tolerance, despite high basal plasma corticosterone levels [10]
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