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Submitted on September 3, 2004
Accepted on October 28, 2004
Boston Biomedical Research Institute (BBRI), 64 Grove St., Watertown, MA 02472; Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston, MA 02114; Harvard Medical School, Boston, MA 02115; Dept of Physiology, Tufts University School of Medicine, Boston, MA 02111
* To whom correspondence should be addressed. E-mail: gonzalezr{at}bbri.org.
Leptin is essential for mouse reproduction but the exact roles it serves are yet to be determined. Treatment of cultured endometrial cells with leptin increases the level of 
3-integrin, interleukin-1 (IL-1), leukemia inhibitory factor (LIF) and their corresponding receptors. These leptin-induced effects are eliminated by inhibitors of leptin receptor (OB-R) signaling. Herein the impact of blocking leptin/OB-R signaling in the mouse endometrium was assessed. Intra-uterine injection of either leptin peptide antagonists (LPA-1 or -2) or OB-R antibody on day 3 of pregnancy impaired mouse implantation in comparison to intra-uterine injection of scrambled peptides (LPA-Sc) or species-matched IgGs. Significant reduction in the number of implantation sites and uterine horns with implanted embryos was found after intra-uterine injection of LPA-1 (1/22) vs. LPA-1Sc (11/15) and LPA-2 (3/17) vs. LPA-2Sc (14/16). The impact of disruption of leptin signaling on the endometrial expression of several molecules in pregnant mice was assessed by Western blot, immunohistochemistry and confocal microscopy. Disruption of leptin signaling resulted in a significant reduction of IL-1 receptor type I (IL-1R tI), LIF-receptor (LIF-R), vascular endothelial growth factor receptor 2 (VEGF-R2/flk-1) and 3-integrin levels. The levels of colony stimulating factor-1 receptor (CSF-1R) and OB-R were unaltered after treatment with LPAs compared with controls. Expression of OB-R protein was pregnancy-dependent and only found in glandular epithelium after implantation occurred. Our findings support previous observations that leptin signaling is critical to the implantation process and suggest that molecules downstream of leptin-activated receptor may serve obligatory roles in endometrial receptivity and successful implantation.
3 integrin •
uterine embryo interaction
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