Although the etiology of preeclampsia (PE) remains unclear, evidence indicates that impaired cytotrophoblast invasion followed by placental ischemia/hypoxia promotes the release of placental anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFlt-1), into the maternal circulation. sFlt-1 blocks the pro-angiogenic actions of vascular endothelial growth factor to elicit maternal endothelial dysfunction and ultimately hypertension and proteinuria. Moreover, a leading risk factor for PE is obesity; however, the mechanisms whereby obesity increases the risk for developing PE are unknown. Our aim was to evaluate circulating and placental sFlt-1 levels in a genetic rodent model of obesity, the melanocortin-4 receptor deficient rat (MC4R+/-). Additionally, we examined the effect of obesity on hypoxia-induced sFlt-1 production in placental villous explants. At gestational day 19, body weight (357±5 vs. 331±11 g) and visceral fat weight (15.3±0.4 vs. 9.2±0.4 g) were higher in MC4R+/- obese pregnant rats (N=7) over MC4R+/+ lean pregnant rats (N=7), whereas mean arterial pressure was similar between groups (MC4R+/-: 110±4 vs. MC4R+/+: 102±2 mmHg). The levels of sFlt-1 in plasma (MC4R+/+: 228±75 vs. MC4R+/+: 141±34 pg/mL) and whole placenta (MC4R+/-: 0.86±0.06 vs. MC4R+/+: 0.82±0.04 pg/mg) were comparable between groups. Similarly, there was no difference in sFlt-1 secretion from 48 h cultures of placental villi explanted from MC4R+/- (1969±176 pg/mg) vs. MC4R+/+ (1408±188 pg/mg) under normoxic conditions (6% oxygen). However, in the face of hypoxia (1% oxygen), there was more pronounced sFlt-1 secretion from MC4R+/- obese rats than MC4R+/+ lean counterparts (2160±233 vs. 1311±120 pg/mg, respectively; P<0.05). In conclusion, we found that sFlt-1 levels were not disrupted in obese pregnant rats during normal pregnancy; however, in vitro studies with placental villi from obese rats showed enhanced hypoxia-induced sFlt-1 secretion. Together these findings suggest that placental ischemia-induced endothelial dysfunction and hypertension may be exaggerated by obesity.