Immunosuppression with tacrolimus improved implantation and rescued expression of uterine progesterone receptor and its co-regulators FKBP52 and PIASy at nidation in the obese and diabetic mice: Comparative studies with metformin.

Diabesity is often associated with subfertility and recurrent miscarriages. Evidence links systemic and local uterine cytotoxicity to the pathogenesis of implantation failure (IF) in diabetes. Immunosuppression with tacrolimus improved pregnancy outcomes in obese and diabetic mice and repeated IF in women with elevated Th1/Th2 blood cell ratios. However the mode of action of tacrolimus in protecting against IF and the molecular mechanisms associated with recurrent miscarriages in the obese and diabetic subjects are yet to be elucidated. Here we administered tacrolimus (FK506) (0.1 mg/kg) for four consecutive weeks to the NONcNZO10/LtJ mice, a model of human PCOS, chronically fed with 60% kCal fat for 16 consecutive weeks to simulate human obesity-associated T2DM. Compared to those immunosuppressed with tacrolimus and their normative controls, high-fat fed (HFD) diabetic NONcNZO mice exhibited higher rates of peri- and post-implantation resorption and had aberrant expression of uterine IFNγ and progesterone receptor (PGR) and its immunophilin co-chaperone FKBP52 at nidation. Immature uterodomes and lack of activation of uterine STAT3 and NFκB at implantation were characteristics of IF in the HFD-dNONcNZO dams also low in the deciduogenic factors IL11 and GM-CSF. Therapeutic interventions with tacrolimus or metformin normalized the expression of decidual IFNγ, PGR and FKBP52, increased co-localization of protein inhibitor of activated STATy (PIASy) to PGR and resulted in the upregulation of uterine IL11and LIF. Rescued phosphorylation of STAT3 and NFκBp65 and uterodome maturation at nidation defined implantation success in treated dams. To our knowledge this is the first report to show that the impact of HFD on the hemochorial implantation is at least in part mediated through disruption of PGR signaling at nidation and that immunosuppression with tacrolimus or treatment with metformin restores PGR-mediated influences during implantation in the obese and diabetic subjects.