Characterization of the role of the TLR4 on the extra pineal production of melatonin and infertility in obese mice

Abstract

During the mounting of inflammatory responses, the bidirectional communication between the pineal gland and the immune system induces the suppression of melatonin production in the pineal to allow the proper migration of macrophages and the initiation of the non-rhythmic production of melatonin in the site where the inflammatory process is occurring. We have shown that the TLR4 plays an important role in controlling melatonin release in the pineal gland (Da Silveira Cruz-Machado et al., 2010, 2012) and in extra-pineal sites (Muxel et al., submitted). The TLR4 is the central regulator of innate immune responses triggered by pathogen- and danger-associated molecular pattern. Free fatty acids and other endogenous ligands induce the low-grade inflammation in obesity through TLR4, which leads to insulin resistance (Pal et al., 2012). On the other hand, TLR4 blockage in the hypothalamus reduces the systemic inflammation, recovers the insulin resistance and improves the physiopathology of obesity (Milanski et al., 2012). However, the role that TLR4 plays in the obesity-induced infertility remains unknown (Fernandez et al., 2011; Erdemir et al., 2012). Our preliminary data shows that obese db/db (leptin receptor deficient) mice, which are well known to be infertile, have higher gene expression of TLR4, pro-inflammatory cytokines and activation of the NF-kB pathway in the testis. In addition, we have observed testicular induction in expression of the key enzyme for melatonin synthesis, the AA-NAT. Here, we propose to evaluate the role of the TLR4 in the activation of the immune-pineal and hypothalamus-pituitary-gonad axis in the model of obesity-induced low-grade inflammation, as well as its role in the reproductive function. (AU)