Metformin Treatment Regulates the Expression of Molecules Involved in Adiponectin and Insulin Signaling Pathways in Endometria from Women with Obesity-Associated Insulin Resistance and PCOS.

Polycystic ovary syndrome (PCOS) is an endocrine/metabolic disorder associated with insulin resistance (IR) and obesity. Endometria from women with PCOS present failures in insulin action, glucose uptake and signaling of insulin-sensitizing molecules, such as adiponectin, with consequences for reproduction. Metformin (MTF) treatment improves insulin signaling in endometrial tissues, but its mechanism is not fully understood. This study addresses the MTF effect, as well as adiponectin agonist action, on levels of molecules associated with insulin and adiponectin signaling pathways in endometrial tissue and cells, as assessed by immunohistochemistry and immunocytochemistry, respectively. Endometrial tissues were obtained from women and divided into five groups: Normal Weight (control); Obesity + IR; Obesity + IR + PCOS; Obesity + IR + MTF; Obesity + IR + PCOS + MTF. Endometrial cells stimulated with TNFα (as obesity-marker) were also used to partially emulate an obesity environment. The results showed low levels of insulin/adiponectin signaling in the endometria from women with obesity, IR and PCOS compared with the control group. MTF re-established these levels, independently of PCOS. TNFα-associated molecules were elevated in pathologic endometria, whereas MTF diminished these levels. The low levels of insulin/adiponectin molecules in endometrial cells treated with TNFα were reverted by MTF, similar to what was observed in the case of the adiponectin agonist. Therefore, independently of PCOS, MTF can re-establish levels of molecules involved in insulin/adiponectin signaling in endometrial cells, suggesting an improvement in insulin action and reproductive failures observed in endometria from women with obesity/PCOS.

A non-genomic signaling pathway shut down by mating changes the estradiol-induced gene expression profile in the rat oviduct.

Estradiol (E(2)) accelerates oviductal egg transport through intraoviductal non-genomic pathways in unmated rats and through genomic pathways in mated rats. This shift in pathways has been designated as intracellular path shifting (IPS), and represents a novel and hitherto unrecognized effect of mating on the female reproductive tract. We had reported previously that IPS involves shutting down the E(2) non-genomic pathway up- and downstream of 2-methoxyestradiol. Here, we evaluated whether IPS involves changes in the genomic pathway too. Using microarray analysis, we found that a common group of genes changed its expression in response to E(2) in unmated and mated rats, indicating that an E(2) genomic signaling pathway is present before and after mating; however, a group of genes decreased its expression only in mated rats and another group of genes increased its expression only in unmated rats. We evaluated the possibility that this difference is a consequence of an E(2) non-genomic signaling pathway present in unmated rats, but not in mated rats. Mating shuts down this E(2) non-genomic signaling pathway up- and downstream of cAMP production. The Star level is increased by E(2) in unmated rats, but not in mated rats. This is blocked by the antagonist of estrogen receptor ICI 182 780, the adenylyl cyclase inhibitor SQ 22536, and the catechol-O-methyltransferase inhibitor, OR 486. These results indicate that the E(2)-induced gene expression profile in the rat oviduct differs before and after mating, and this difference is probably mediated by an E(2) non-genomic signaling pathway operating on gene expression only in unmated rats.