Pregnancy is a state of physiological hyperphagia and represents a good model to unravel the mechanisms involved in feeding regulation. The hyperphagia is the main responsible for the positive energy balance in gestation, which is necessary for maintaining maternal energy stores. The presence of high serum leptin levels and hyperphagia during pregnancy is a paradoxical event and reflects a state of leptin resistance. In order to evaluate the mechanisms for hypothalamic leptin resistance during pregnancy, we evaluated the response of food intake, hypothalamic neuropeptides, and p-STAT3 levels to leptin administration in pregnant rats.
Diestrous and pregnant rats (13 and 18 of gestation) were used in this study. Icv and iv cannulae were implanted into third ventricle or in jugular vein respectively, five days before treatments (icv:10 μg/rat, iv:100 μg/rat). Nocturnal food intake was determined in rats fasted 6 hours before vehicle or leptin treatment. NPY and AgRP mRNA levels were determined by in situ hybridization using specific antisense oligodeoxynucleotide probes labeled with 35S. Levels of p-STAT3 were determined by western blot in rats fasted overnight which received iv or icv leptin for one hour.
1) Pregnant rats exhibited a lack of decrease in the nocturnal food intake after icv leptin treatment.
2) Pregnant rats presented higher levels of NPY and AgRP in the hypothalamus, but we could not demonstrate a decrease in their levels after leptin treatment.
3) Administration of leptin iv and icv showed a clear increase in the levels of p-STAT3 in control rats but not in pregnant rats.
All this indicates that a reduction in leptin signalling in the hyphothalamus likely contributes to the leptin resistance mechanism during pregnancy.