Postnatal Diet-Induced Obesity in Rats Upregulates Systemic and Adipose Tissue Glucocorticoid Metabolism During Development and in Adulthood

Abstract

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...

Postnatal Programming of Glucocorticoid Metabolism in Rats Modulates High-Fat Diet–Induced Regulation of Visceral Adipose Tissue Glucocorticoid Exposure and Sensitivity and Adiponectin and Proinflammatory Adipokines Gene Expression in Adulthood

“…It is established that glucocorticoids stimulate 11␤-HSD-1 gene expression (37). We previously demonstrated that postnatal overfeeding induced MAT GR mRNA upregulation, which was detectable as soon as day 21 of life and preceded that of 11␤-HSD-1, suggesting that a diet-induced programming of GR gene expression, possibly of epigenetic origin (38), was the primary phenomenon (20). Such a phenomenon may account for the reversal of the decrease in MAT GR mRNA expression found in programmed rats fed high-fat diet.…”

“…Assays. Corticosterone was assayed in urine after dichloromethane extraction using a radioimmunoassay, as previously described (20). Plasma glucose and free fatty acids (FFAs) were measured using enzymatic methods (Biomé rieux, Marcy l'Etoile, France, and Oxoid, Dardilly, France, respectively).…”

“…Prenatal dexamethasone exposure resulted in glucose intolerance, hyperinsulinemia, high blood pressure, and exaggerated cortisol response to stress in nonhuman primate offspring (19). We have shown that postnatal overfeeding in rats, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for endocrine maturation such as late gestation in humans, is followed in adulthood by a moderate overweight status, significant metabolic disturbances comparable with those described in the metabolic syndrome, and upregulation of basal and stress-induced systemic glucocorticoid secretion and of adipose tissue exposure and sensitivity (20). We hypothesized that postnatal programming of glucocorticoid metabolism in rats could modulate high-fat diet-induced adipose tissue dysregulation in adulthood.…”

Low expression of insulin signaling molecules impairs glucose uptake in adipocytes after early overnutrition

“…Despite these alterations, our results showed no differences in glucose tolerance test in rats raised under different feeding conditions. However, Plagemann et al (1999b) and Boullu-Ciocca et al (2005) have demonstrated alterations in glucose tolerance test in animals raised in SL at 120 and 250 days of age respectively. These data suggest that early postnatal overfeeding may induce insulin resistance in later life.…”

“…The results showed that blood glucose and plasma insulin levels, as well as plasma lipid levels, are similar between the animals raised in different litter size. However, Boullu-Ciocca et al (2005) described how adult animals (age 120 days) neonatally overfed show increased insulin and insulin/glucose ratio, whereas fasting glycemia was not changed. In agreement with this, it has been shown that neonatally overfed rats present significant metabolic disturbances in adulthood, such as increased systolic blood pressure and impaired glucose tolerance (Cryer & Jones 1980, You et al 1990, Plagemann et al 1992, Boullu-Ciocca et al 2005.…”