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Abstract Glucocorticoids increase appetite and body weight gain in rats and ovariectomy (OVX) induces obesity, while estrogen (E) replacement attenuates OVX-induced changes. It is known that animals with obesity are more responsive to glucocorticoids anabolic effects than lean ones. This study aimed to evaluate the effects of ovariectomy and the protective role of estradiol on the responses induced by prolonged treatment with corticosterone or dexamethasone on energy homeostasis. For this, female Wistar rats subjected to SHAM or OVX surgery, composing the SHAM, OVX, and OVX + E groups, received water/ETOH or corticosterone (15 mg/l) and water or dexamethasone (0.5 μg/l) as drinking fluid for 28 days. The OVX + E group, since the first day, was daily treated with estradiol (10 μg/0.2 ml/rat SC). OVX induced enhancement of body weight gain, food intake, area of the adipocytes and weight of retroperitoneal adipose tissue, plasma cholesterol and glucose intolerance, with reduction on uterus weight. In OVX animals, treatment with glucocorticoids induced increases on body weight gain, food intake, weight of retroperitoneal adipose tissue, area of adipocytes of retroperitoneal and perigonadal + perirenal fat depots, plasma triglycerides (corticosterone), and glycemic response after GTT (dexamethasone), with minor effects on SHAM group. Estradiol treatment to OVX rats prevented these effects induced by glucocorticoids, in addition to decrease body weight gain, fat accumulation and glucose intolerance, and to increase weight of uterus, triglycerides and free fatty acids plasma levels. These data demonstrate that protection against glucocorticoids-induced anabolic responses in females is eliminated by ovariectomy and estradiol can prevent these responses. [ABSTRACT FROM AUTHOR]

Litter size reduction on the first days of life results in increased body weight and adiposity, with higher levels of circulating glucocorticoids. Obese rodents are more sensitive to the anabolic effects of glucocorticoids and less responsive to glucocorticoids feedback on hypothalamic-pituitary-adrenal (HPA) axis. This study aimed to evaluate effects of the treatment with corticosterone on metabolic responses and HPA axis in adult male rats reared in small litters. From postnatal day (PND) 60 to 88, adult male rats of normal (NL- 10 pups/dam) and small (SL- 3 pups/dam) litters received oral treatment with Corticosterone (CORT-15 mg/L) in the drinking water or no treatment, composing the four experimental groups (NL-water; NL-CORT; SL-water and SL-CORT), for the evaluation of energy homeostasis and HPA axis. Male rats of SL-water group presented on PND88: glucose intolerance, higher adiposity, plasma triglycerides, free fatty acids, total and low-density lipoprotein (LDL) cholesterol and corticosterone. SL-water animals showed increased mRNA of corticotrophin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) and proopiomelanocortin (POMC) in the pituitary, with decreased mRNA expression of PVN mineralocorticoid receptor. NL-CORT animals presented glucose intolerance, increased body weight, food intake, total and LDL cholesterol. Glucocorticoid treatment reduced corticosterone levels and adrenal cortex thickness in NL group, associated with increased mRNA of PVN CRH and pituitary POMC, without effects on SL animals. Lactation overnutrition promotes hyperreactivity of HPA axis and reduces the responsiveness to glucocorticoids effects on energy balance and negative feedback of HPA axis in adult male rats. Schematic diagram demonstrating that 1) corticosterone treatment in rats from normal litters (NL) caused metabolic changes (higher body weight, food intake, increased plasma levels of total and LDL cholesterol, and glucose intolerance) and adrenal gland atrophy, as observed by reduced thickness of adrenal cortex and corticosterone plasma levels, which induced higher expression of corticotrophin-releasing hormone (CRH) in the paraventricular nucleus of hypothalamus (PVN) and proopiomelanocortin (POMC) in the pituitary, due to the lack of negative feedback of glucocorticoids; 2) Male rats raised in small litters (SL) exhibited metabolic changes (glucose intolerance, adiposity, and dyslipidemia) and hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis (higher expression of CRH in the PVN, POMC in the pituitary and corticosterone plasma levels, associated with lower expression of MR in the PVN); 3) Obesity induced by litter size reduction impaired glucocorticoids effects on energy balance and HPA axis. [Display omitted] • Litter size reduction induced obesity-related changes in adult male rats. • Early overnutrition induced hyperactivity of HPA axis and lower PVN MR expression. • Reduction of litter size impaired metabolic changes of exogenous glucocorticoids. • Neonatal overnutrition disrupted negative feedback of glucocorticoids on HPA axis. [ABSTRACT FROM AUTHOR]

This work evaluated the effects of neonatal overfeeding, induced by litter size reduction, on fertility and the noradrenaline-kisspeptin-gonadotrophin releasing hormone (GnRH) pathway in adult female rats. The litter size was adjusted to 3 pups with each mother in the small litters (SL) and 10 pups with each mother in the normal litters (NL). SL females exhibited metabolic changes associated with reproductive dysfunctions, shown by earlier vaginal opening and first estrus, later regular cyclicity onset, and lower and higher occurrences of estrus and diestrus phases, respectively, as well as reduced fertility, estradiol plasma levels, and mRNA expressions of tyrosine hydroxylase in the locus coeruleus, kisspeptin, and GnRH in the preoptic area in adult females in the afternoon of proestrus. These results suggest that neonatal overfeeding in female rats promotes reproductive dysfunctions in adulthood, such as lower estradiol plasma levels associated with impairments in fertility and noradrenaline-kisspeptin-GnRH pathway during positive feedback. Graphical Abstract. Schematic diagram demonstrating that neonatal overfeeding induced by litter size reduction in female rats caused metabolic alterations: higher body weight, Lee index, adiposity, free fatty acids and corticosterone plasma levels, and glucose intolerance. These effects were associated with reproductive dysfunctions: earlier vaginal opening and first estrus, delayed estrous cycle regularization, estrous cycle dysregulation, as well as lower plasma estradiol concentrations related to reduced fertility and tyrosine hydroxylase (TH) mRNA expression in the locus coeruleus (LC), and kisspeptin (Kiss) and gonadotropin releasing hormone (GnRH) mRNA expression in the preoptic area (POA) in adult females in the afternoon of proestrus. Image 1 • Litter size reduction induced reproductive dysfunctions in female rats. • Obesity induced by neonatal overnutrition advanced puberty in females. • Reduction of litter size caused dysregulation of estrous cycle. • Neonatal overnutrition reduced estradiol plasma levels and fertility. [ABSTRACT FROM AUTHOR]