|dc.description.abstract||Leptin is an adipose-derived hormone that acts in the hypothalamus to regulate energy homeostasis by decreasing appetite and increasing metabolic rate. During pregnancy, food intake and fat deposition increases, despite elevated leptin levels, suggesting a state of leptin resistance. The aim of this thesis is to determine whether mice become resistant to leptin during pregnancy. This would facilitate use of transgenic animals to elucidate the mechanism of pregnancy-induced leptin resistance. To examine this we looked at food intake in response to leptin administration, and the effect of leptin on the expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the hypothalamus of pregnant mice.
To establish normal eating patterns throughout the mouse reproductive cycle, food, water intake and body weight were monitored during the estrous cycle, pregnancy and early lactation. To investigate whether pregnant mice remained responsive to the satiety effects of leptin, food intake was measured after an intraperitoneal (i.p.) leptin or vehicle injection in fasted mid-pregnant (day 13) mice and compared to non-pregnant (diestrous) mice. Leptin treatment significantly reduced food intake in the non-pregnant mice while no effect was seen in the pregnant mice. This indicates that mice become resistant to the appetite suppressant effects of leptin during pregnancy.
To quantify hypothalamic leptin resistance in the pregnant mouse, pSTAT3, a marker of leptin signal transduction, was measured in mid-pregnant and non-pregnant mice following i.p. administration of leptin. In all regions examined in both the pregnant and non-pregnant mice, leptin treatment induced significant pSTAT3 expression compared to vehicle treatment. However, in the ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH), leptin treatment induced significantly less pSTAT3 expression in pregnant compared to nonpregnant mice. In contrast, in the arcuate nucleus there was no significant difference in expression of pSTAT3 following leptin treatment between pregnant and non-pregnant mice.
These data support the hypothesis that pregnancy in the mouse is a leptin resistant state associated with impaired leptin-induced signal transduction, involving the JAK/STAT pathway, specifically in the VMH and DMH. This is an adaptive maternal response to provide sufficient energy stores for the metabolically demanding tasks of pregnancy and lactation. Maternal obesity is a significant health concern that is exacerbated by this physiological adaptation with considerable side effects for both mother and baby. Gaining a better understanding of pregnancy-induced leptin resistance provides an opportunity to help in the management of this topical issue.||