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.