Obesity Reduces Endometrial Receptivity by Downregulating the Ob-Rb/STAT-3 Signaling Pathway in Women and Female Mice.

OBJECTIVE

Obesity impairs endometrial receptivity; however, the mechanism remains unclear. Obesity is associated with elevated leptin levels, and leptin receptor (Ob-Rb) has been demonstrated to be expressed in the human endometrium, but the mechanistic pathway of leptin and endometrial dysfunction has not yet been explored.

METHODS

In a human study, serum leptin levels and expressions of Ob-Rb, signal transducers and activators of transcription (STAT-3), and endometrial receptivity factors [leukemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF)] were compared in midsecretory phase endometrium among normal-weight, overweight, and obese women. In an animal study of a diet-induced obesity (DIO) mouse model, a leptin resensitization mouse model and Ob-Rb inhibitor mouse model were established.

RESULTS

Serum leptin levels were higher in women with overweight/obesity and female DIO mice compared with those with normal weight. The expressions of Ob-Rb, pSTAT-3, and the endometrial receptivity factors of LIF and VEGF were decreased in obese women and DIO mice. Pregnancy rates and the average blastocyst numbers were lower in DIO mice than those in normal-weight mice. After leptin resensitization in DIO mice, the expression of Ob-Rb, pSTAT-3, and endometrial receptivity were increased, whereas these were all decreased in the Ob-Rb inhibitor mouse model compared with normal-weight mice.

CONCLUSION

Obesity-induced Ob-Rb/STAT-3 signaling dysfunction is a central mechanism impairing endometrial receptivity. Leptin resensitization via weight loss partially reverses these effects, suggesting potential therapies for targeting leptin resistance or Ob-Rb/STAT-3 signaling in obesity-related infertility.