Metformin treatment regulates the expression of molecules involved in adiponectin and insulin signaling pathways in endometrium from women with obesity-associated insulin resistance and PCOS.

Polycystic Ovary Syndrome (PCOS) is an endocrine and metabolic disorder closely associated with insulin resistance (IR) and obesity. Studies have been shown that endometrium from women with PCOS presents failures in insulin action, glucose uptake and signaling of insulin-sensitizer molecules as adiponectin, which could explain the reproductive failures observed in these women. Treatment with Metformin (MTF) can reverse some alterations associated with insulin signaling in endometrial tissues, but the mechanism by which MTF can enhance insulin action in endometrial cells is not fully understood. Here, the effect of MTF on the expression of molecules associated with insulin and adiponectin signaling in endometrial tissue and cells exposed to conditions that partly emulate obesity was evaluated. For this, endometrial tissue obtained from five women groups was used: Normal-Weight (control group), Obesity+IR, Obesity+IR+PCOS, Obesity+IR+MTF and Obesity+IR+PCOS+MTF. Both IR women groups were treated with MTF for at least 12 weeks. Also, we used a cell line of human endometrial cells stimulated with TNFα (an obesity marker) to partially emulate an obesity environment. Endometrial tissues and cells were used to evaluate the effect of MTF on insulin and adiponectin molecules signaling by immunohistochemistry and immunocytochemistry, respectively. Finally, we evaluated the effect of an adiponectin agonist (AdipoRon) on insulin and adiponectin signaling molecules in endometrial cells treated with TNFα. The results show that insulin and adiponectin molecules signaling were diminished in endometrium from women with obesity, IR and PCOS compared with control group. However, these levels were re-established with MTF treatment, independent of PCOS. Interestingly, molecules associated with TNFα action were elevated in pathologic endometrium, whereas MTF diminished these levels. The cellular model also showed that TNFα decreased levels of molecules related to insulin and adiponectin, whereas MTF can revert these levels to basal condition. The same effect was observed with AdipoRon on insulin and adiponectin molecules signaling in endometrial cells treated with TNFα. The results indicate that independent of PCOS, MTF (or adiponectin agonist) can re-establish levels of molecules involved in insulin action in endometrial cells, could improving the reproductive failures observed in women with obesity and PCOS.