Oxytocin participates on the effects of vasoactive intestinal peptide on food intake and plasma parameters.

Vasoactive intestinal peptide (VIP) is a neurotransmitter with anorectic effect that acts in the hypothalamus to regulate food intake. Oxytocin is a neuropeptide produced in the hypothalamus that controls energy homeostasis and has an inhibitory role on food intake. Thus, the present study aims at verifying the role of oxytocin as a mediator of VIP on energy homeostasis. For this purpose, intracerebroventricular microinjection of oxytocin receptor antagonist (vasotocin, OVT) or vehicle (NaCl 0.9%) was carried out in male rats, and after 15 min, VIP or saline was microinjected. After 15 min of the second microinjection, food intake was evaluated or euthanasia was undertaken for blood collection. There was a reduction on food intake after VIP microinjection and the pretreatment with OVT partially reversed this effect. Hyperglycemia was observed after VIP microinjection, and pretreatment with OVT partially blocked this effect. Plasma corticosterone concentration was significantly increased after VIP or OVT. Plasma levels of free fatty acids were decreased by VIP, but not when VIP was microinjected after OVT. Thus, OVT partially reversed VIP-induced hypophagia and changes on plasma metabolic parameters, suggesting a role for oxytocin as a mediator of VIP effects on energy homeostasis.

Glucocorticoids contribute to metabolic and liver impairments induced by lactation overnutrition in male adult rats.

Introduction: Lactation overnutrition is a programming agent of energy metabolism, and litter size reduction leads to the early development of obesity, which persists until adulthood. Liver metabolism is disrupted by obesity, and increased levels of circulating glucocorticoids are pointed as a possible mediator for the obesity development, since bilateral adrenalectomy (ADX) can reduce obesity in different models of obesity. Methods: This study aimed to evaluate the effects of glucocorticoids on metabolic changes and liver lipogenesis and insulin pathway induced by lactation overnutrition. For this, on the postnatal day 3 (PND), 3 pups (small litter-SL) or 10 pups (normal litter-NL) were kept with each dam. On PND 60, male Wistar rats underwent bilateral adrenalectomy (ADX) or fictitious surgery (sham), and half of ADX animals received corticosterone (CORT- 25 mg/L) diluted in the drinking fluid. On PND 74, the animals were euthanized by decapitation for trunk blood collection, and liver dissection and storage. Results and Discussion: SL rats presented increased corticosterone, free fatty acids, total and LDL-cholesterol plasma levels, without changes in triglycerides (TG) and HDL-cholesterol. The SL group also showed increased content of liver TG, and expression of fatty acid synthase (FASN), but decreased expression of PI3Kp110 in the liver, compared to NL rats. In the SL group, the ADX decreased plasma levels of corticosterone, FFA, TG and HDL cholesterol, liver TG, and liver expression of FASN, and IRS2, compared to sham animals. In SL animals, CORT treatment increased plasma levels of TG and HDL cholesterol, liver TG, and expression of FASN, IRS1, and IRS2, compared with the ADX group. In summary, the ADX attenuated plasma and liver changes observed after lactation overnutrition, and CORT treatment could reverse most ADX-induced effects. Thus, increased circulating glucocorticoids are likely to play a pivotal role in liver and plasma impairments induced by lactation overnutrition in male rats.

Lactation overnutrition-induced obesity impairs effects of exogenous corticosterone on energy homeostasis and hypothalamic-pituitary-adrenal axis in male rats.

AIMS: 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. MAIN METHODS: 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.

Neonatal overfeeding reduces estradiol plasma levels and disrupts noradrenergic-kisspeptin-GnRH pathway and fertility in adult female rats.

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.

WITHDRAWN: Sex differences in glucocorticoids-induced anabolic effects on energy balance.

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been withdrawn at the request of the editor and publisher. The publisher regrets that an error occurred which led to the premature publication of this paper. This error bears no reflection on the article or its authors. The publisher apologizes to the authors and the readers for this unfortunate error.

Sex differences in glucocorticoids-induced anabolic effects in rats.

Glucocorticoids (GC) increase food intake and body weight in humans and rodents and chronic stress and GC treatment-induced enhancement of the plasma concentration of GC lead to obesity and metabolic changes. In response to hypercaloric treatment, males were shown to be more susceptible to obesity than females, demonstrating that sex differences may affect energy homeostasis. The objective of the current study was to evaluate the effects of prolonged (28 days) treatment with dexamethasone or corticosterone on food intake and body weight gain in intact rats, both male and female. Also examined were Lee index, weights and area of adipocytes of retroperitoneal and perigonadal+perirenal adipose tissues, glucose tolerance test (GTT) and plasma concentrations of free fatty acids, cholesterol and triglycerides. Treatment with dexamethasone was able to increase body weight, food intake, area of adipocytes and weight of retroperitoneal adipose tissue in males. Prolonged treatment with corticosterone also stimulated body weight gain and food intake in males. In addition, it induced an increase in the area of adipocytes and weight of perirenal+perigonadal adipose tissue and higher glycemia after GTT in these animals, without changes on Lee index and plasma parameters after both GC treatments. No parameter was changed by dexamethasone or corticosterone treatment in female rats. Thus, it can be concluded that male rats are more susceptible to the anabolic effects of glucocorticoids than female rats, and these responses can be due to the protective effects of circulating estrogens in females, and/or the difference between males and females in the expression/activity of corticosteroids receptors.

Estradiol protects against ovariectomy-induced susceptibility to the anabolic effects of glucocorticoids in rats.

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.