Maternal prolactin inhibition during lactation is associated to renal dysfunction in their adult rat offspring.

The renal function of rats whose mothers had hypoprolactinemia at the end of lactation was evaluated during development. Lactating Wistar rats were treated with bromocriptine (BRO, 1 mg twice a day, s.c.) or saline on days 19, 20, and 21 of lactation, and their male offspring were followed from weaning until 180 days old. 1 rat from each of the 12 litters/group was evaluated at 2 time points (90 and 180 days). Body and kidney weights, sodium, potassium, and creatinine were measured. Values were considered significant when p<0.05. Adult BRO-treated offspring presented higher body weight (+10%), lower relative renal weight at 90 and 180 days (-9.2% and -15.7%, respectively), glomerulosclerosis, and peritubular fibrosis. At 90 and 180 days, creatinine clearance was lower (-32% and -30%, respectively), whereas serum potassium was higher (+19% and +29%, respectively), but there were no changes in serum sodium. At 180 days, higher proteinuria (+36%) and serum creatinine levels (+20%) were detected. Our data suggest that prolactin inhibition during late lactation programs renal function damage in adult offspring that develops gradually, first affecting the creatinine clearance and potassium serum levels with further development of hyperproteinuria and higher serum creatinine, without affecting sodium. Thus, precocious weaning programs some components of the metabolic syndrome, which can be a risk factor for further development of kidney disease.

Blocking leptin action one week after weaning reverts most of the programming caused by neonatal hyperleptinemia in the adult rat.

Hyperleptinemia during lactation programs for higher serum leptin in 30-day-old and adult rats, associated with metabolic changes. Here we evaluated the inhibition of serum leptin at 29 and 30 days on the metabolic phenotype of rats programmed with leptin during lactation. Pups from Wistar rats were saline-injected or leptin-injected from postnatal day 1 to day 10. At 29 and 30 days old, animals were injected with anti-leptin antibody (LA and CA) or saline (LS and CS). In adult animals, higher visceral (+53%) and total fat mass (+33%), hyperleptinemia (+67%), hypertriglyceridemia (+47%), and hypoadiponectinemia (-44%) observed in LS group compared to CS were prevented by immunoneutralization of leptin, since LA group had those parameters values similar to CS group. However, immunoblockade of leptin in normal animals led to the same metabolic changes seen in leptin-treated animals, in addition to lower serum adiponectin (-77% vs. CS) and higher insulin resistance index (+37%). Liver sirtuin1 (SIRT1) was higher (+41%) only in LA group, suggesting a role for SIRT1 in the prevention of leptin programming. Hypothalamic OBR was lower and SOCS3 higher in LS group and these changes were normalized in LA group. In conclusion, blocking leptin action one week after weaning seems to revert most of the alterations observed in rats programmed by neonatal hyperleptinemia. Higher liver SIRT1 expression may be one of the mechanisms involved, leading to a better glucose and lipid metabolism. Our data suggest that the lack or the excess of leptin programs an adverse metabolic phenotype in adulthood.

Early maternal hyperleptinemia programs adipogenic phenotype in rats.

We have previously reported on the treatment of maternal rats with leptin during the three last days of lactation program for overweight and leptin hypothalamic resistance in the offspring. Here we have investigated whether treatment of maternal rats with leptin in the first ten days of lactation can program metabolic dysfunctions on the adult offspring. Lactating rats were divided into 2 groups: rats (LEP) injected with recombinant mouse leptin (8 microg/100 g/body weight, daily during the first 10 days of lactation) and control group (C) that received the same volume of saline. After weaning, all pups had free access to normal diet, their body weight and food intake were monitored at 4 days interval until 180 days, when they were tested for food intake and response to either leptin (0.5 mg/kg body weight, ip) or saline. The offspring from leptin-treated mothers gained more weight from day 69 onward and had higher food intake from day 145 onward, higher amount of visceral adipose tissue (57%), higher serum glucose (10%), and higher serum leptin (135%) at 180 days compared to control group. The food intake was not reduced as expected after acute injection of leptin in these animals, suggesting resistance to the anorexigenic effect of leptin. We conclude that maternal hyperleptinemia in early lactation programed higher food intake, body weight gain due to higher total and visceral fat mass, and resistance to anorexigenic effect of leptin in the adult offspring even when this hyperleptinemia occurred at the beginning of lactation.