Poster Presentation The International Congress of Neuroendocrinology 2014

Impaired hypothalamic leptin sensitivity in pseudopregnant rats treated with chronic prolactin to mimic pregnancy. (#351)

Pene J Knowles 1 , Rachael A Augustine 1 , Zin Khant Aung 1 , Sharon R Ladyman 1 , Dave R Grattan 1
  1. University of Otago, Dunedin, New Zealand

Pregnancy in rodents is associated with hyperphagia, increased fat deposition, elevated leptin concentrations and insensitivity to the satiety action of leptin. To investigate the hormonal mechanisms involved in the development of this state of pregnancy-induced leptin resistance we have previously demonstrated that pseudopregnant rats have a normal feeding response to leptin. However, if the state of pseudopregnancy is extended by progesterone and chronic i.c.v. ovine prolactin infusion, to model the placental lactogen secretion of mid pregnancy, then leptin no longer suppresses food intake, thus implicating high lactogen concentrations in the development of pregnancy-induced leptin resistance. To further investigate this effect of chronically high lactogen levels, leptin-induced activation of hypothalamic JAK/STAT signal transduction was examined in pseudopregnant rats infused with chronic ovine prolactin. Groups of virgin (diestrous) and pseudo-pregnant rats were treated with chronic i.c.v. infusion of either prolactin (2.5 μg/μl/hr for 5 days) or vehicle (aCSF) via a minipump connected to a cannula surgically implanted into the lateral ventricle. After 5 days, rats were fasted overnight then received an i.c.v. injection of leptin (400 ng) or vehicle (aCSF), and perfused 30 minutes later. Coronal sections through the hypothalamus were processed for immunohistochemistry for phospho-STAT3 and the number of cells stained positively for phospho-STAT3 were counted in each area of interest. In diestrous rats, independent of whether they were chronically infused with prolactin or vehicle, i.c.v. leptin treatment lead to an increase in the number of phospho-STAT3 positive cells in the VMH and arcuate nucleus. In chronic vehicle infused pseudopregnant rats, i.c.v. leptin increased the number of phospho-STAT3 positive cells, however this effect of leptin was not observed in the pseudopregnant rats that were chronically infused with prolactin. These data suggest that central leptin resistance due to chronically high lactogen levels is associated with impaired leptin-induced activation of the JAK/STAT pathway in the hypothalamus.