Characterization of the Reproductive Effects of the <b><i>Vgf</i></b>-Derived Peptide TLQP-21 in Female Rats: In vivo and in vitro Studies

Abstract

Background: VGF (non-acronymic), a protein expressed in the hypothalamus and pituitary, is involved in the control of metabolism and body weight homeostasis. Different active peptide fragments are generated from VGF, including TLQP-21. Previous studies of our group reported that this molecule participates also in the regulation of reproductive function in male rats, with predominant stimulatory effects. Methods: We report herein a series of studies on the reproductive effects of TLQP-21 in female rats, as evaluated by a combination of in vivo and in vitro analyses. Results: TLQP-21 modestly increased serum LH levels after systemic administration and directly stimulated pituitary LH and FSH secretion in prepubertal female rats, while acute central injection of TLQP-21 was unable to modify LH secretion at this age. Repeated central administration of TLQP-21 during the pubertal transition (between PND-28 and -35) to female rats fed ad libitum advanced the timing of vaginal opening and increased the percentage of animals with signs of ovulation. Moreover, an analogous treatment slightly enhanced ovarian maturation in pubertal female rats subjected to chronic undernutrition, but was unable to rescue the delay of vaginal opening induced by food deprivation. In addition, TLQP-21 oppositely modified LH secretion in adult female rats depending on the stage of the ovarian cycle: it stimulated LH secretion when injected in the morning of diestrus and decreased the magnitude of the preovulatory LH (but not FSH) surge when injected in the afternoon of proestrus. Conclusions: Our data are the first to document the potential involvement of TLQP-21 in the control of reproductive function in female rats.

Identification of the C3a Receptor (C3AR1) as the Target of the VGF-derived Peptide TLQP-21 in Rodent Cells

“…Interestingly, like CHO-K1 cells, O-342 cells are of ovarian origin, suggesting a potential novel role of TLQP-21 in reproduction. This appears to be consistent with a recent publication reporting TLQP-21 effects on reproduction in female rats (33).…”

Pharmacological and Biochemical Characterization of TLQP-21 Activation of a Binding Site on CHO Cells

“…Moreover, we have recently demonstrated TLQP-21 binding sites on CHO cells through the use of Atomic Force Microscopy (Cassina et al, 2013). Interestingly, the rat ovary express high levels of TLQP-21, which has been proposed to affect female reproduction by modulating pituitary LH release (Aguilar et al, 2013; Noli et al, 2014) The statistical distribution of the attractive force between TLQP-21 and its binding site is indicative of a single class of binding sites. This presence of a TLQP-21 binding site in these cells is consistent with their unique dose- and time-dependent increases of intracellular calcium (Ca 2+ ) mobilization in response to TLQP-21 (Cassina et al, 2013).…”

The TLQP-21 Peptide Activates the G-Protein-Coupled Receptor C3aR1 via a Folding-upon-Binding Mechanism

“…The best studied fragment is the C-terminal internal peptide designated TLQP-21, whose sequence and function we have identified and extensively characterized (Bartolomucci et al, 2006). TLQP-21 is a multifunctional peptide that regulates energy balance (Bartolomucci et al, 2006, Jethwa et al, 2007, Possenti et al, 2012), glucose metabolism (Stephens et al, 2012), gastric function (Severini et al, 2009), nociception (Rizzi et al, 2007, Chen et al, 2013, Fairbanks et al, 2014), blood pressure regulation (Fargali et al, 2014), reproduction (Aguilar et al, 2013) and stress (Razzoli et al, 2012). Importantly, it was found that a central infusion of TLQP-21 increases energy expenditure and prevents obesity in rodents (Bartolomucci et al, 2006, Jethwa et al, 2007).…”