The neuropeptide Y Y1 receptor mediates NPY‐induced inhibition of the gonadotrope axis under poor metabolic conditions

Abstract

Hypothalamic neuropeptide Y (NPY) plays a central role in the control of food intake, energy balance, and modulation of neuroendocrine functions. In particular, an increase in NPY expression participates in the inhibition of the reproductive activity under poor nutritional conditions. The present study was designed to evaluate further the involvement of the Y1 subtype of NPY receptors in these effects. Food intake, body weight gain, and the onset of puberty were studied in groups of wild-type and Y1 deficient mice that were either fed ad libitum or subjected to a 30% restriction in food intake. This moderate feeding restriction induced a similar deficit in body weight gain in wild-type and in Y1 knockout mice. However, although wild-type mice experienced the expected delay of puberty, all mice in the food restriction group and lacking Y1 could go through puberty over the time of the experiment despite decreases in circulating leptin levels and increases in hypothalamic NPY expression. This observation demonstrates that the absence of Y1 impairs the perception of decreasing energy stores by the gonadotrope axis, demonstrating a physiological role for Y1 in the sensing of endogenous metabolic parameters by the hypothalamus.

Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty

“…For example, GABA, glutamate, and NPY are considered important candidates (Plant, 2001;Terasawa and Fernandez, 2001) alongside potential roles for glial-derived signaling molecules (Ojeda et al, 2003). Although deletions or manipulations of these molecules may delay puberty in mice (Gonzales et al, 2004;Prevot et al, 2005), to our knowledge, the GPR54 knock-out mouse is the only model in which the complete absence of puberty is manifest as an isolated phenotype. This suggests that kisspeptin-GPR54 is high in the hierarchy of components within the GnRH neuronal network critical for puberty onset.…”

Kisspeptin Directly Regulates Neuropeptide Y Synthesis and Secretion via the ERK1/2 and p38 Mitogen-Activated Protein Kinase Signaling Pathways in NPY-Secreting Hypothalamic Neurons

“…Current literature suggests that a substantial part of the actions of kisspeptin on GnRH are conducted via direct activation of GnRH neurons because the majority of GnRH neurons (ϳ70%) express Kiss1r (7) and kisspeptin is the most potent stimulator of gonadotropin release known to date (37). Likewise, NPY is less potent than kisspeptin in stimulating LH release (21) and may have inhibitory effects on the gonadotropic axis under certain conditions (27)(28)(29)(30)(31)(32). Therefore, we suggest that the proposed indirect actions of kisspeptin on GnRH neurons via afferent NPY neurons may play a more complementary role to the direct stimulatory effect of kisspeptin on GnRH release.…”

“…Both in vivo and in vitro studies have demonstrated that NPY stimulates GnRH secretion (20 -26), because NPY infusion into the third ventricle of ewes significantly elevated GnRH levels in the median eminence (23), and exposure of NPY to GT1-7 cells significantly increases GnRH secretion (24). Although the stimulatory effect of NPY on GnRH neurons has been well-documented, NPY can also have an inhibitory action on GnRH release, which is associated with changes in steroidal environment, stage of development, and species (27)(28)(29)(30)(31)(32). For instance, intrahypothalamic perfusion of NPY decreased mean GnRH levels in ovariectomized rats, whereas the same NPY perfusion stimulated mean GnRH levels in intact rabbits (32).…”

Caloric restriction: Impact upon pituitary function and reproduction

“…When the somatic NPY Y4 receptor subtype is knocked out, this prevents CR-induced changes in hypothalamic GnRH expression and peripheral testosterone levels (Lin et al, 2007). In addition to the Y4 receptor subtype, it seems that the integration of energy intake and reproductive function also relies in part on Y1 type receptor activation, as Y1 receptor knock-out animals have also been shown to possess a reproductive axis that is resistant to mild chronic CR (Gonzales et al, 2003). As well as being involved in responses to chronic energy shortages, NPY Y1 receptor activation also seems to integrate acute fasting to short-term disruption of the gonadotrope axis (Pralong et al, 2002).…”