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The neuropeptide Y Y1 receptor mediates NPY-induced inhibition of the gonadotrope axis under poor metabolic conditions¹

Division of Endocrinology, Diabetology and Metabolism and
^* Division of Hypertension, University Hospital, Lausanne, Switzerland

²Correspondence: Division of Endocrinology, BH 19-709, University Hospital, 1001 Lausanne, Switzerland. E-mail: Francois.Pralong{at}chuv.hospvd.ch

SPECIFIC AIMS

We investigated the physiological importance, for the central modulation of metabolism and reproduction, of the hypothalamic NPY neuronal system and its downstream pathways involving Y1. Food intake, body weight gain, and the timing of onset of puberty were studied in juvenile female mice until day 50 of age. Experiments were performed in groups of wild-type and Y1-deficient mice that either had free access to food or were allowed to eat only 70% of the amount taken by the ad lib fed controls (pair feeding).

PRINCIPAL FINDINGS

1. Mice lacking Y1 do not gain weight normally in the prepubertal period
Y1-deficient mice and wild-type controls have identical weights at birth but weigh less than wild-type controls at the time of weaning. This difference had disappeared by the day of vaginal opening, indicative of an abnormal weight gain during the prepubertal period in Y1-deficient mice. The defective growth of Y1 knockouts was independent of feeding.

2. Hypothalamic NPY participates to the neuroendocrine adaptations to a moderate degree of chronic underfeeding
An up-regulation of hypothalamic NPY expression has been shown to play a pivotal role in the neuroendocrine response to an acute (24 to 48 h) fast. In the present study, mice were subjected to a less stringent restriction of caloric intake than fasting. We could show that even a 30% decrease in food intake is associated with increases in hypothalamic NPY expression of similar magnitude in fed-restricted wild-type and Y1 knockout mice.

3. The absence of Y1 protects the gonadotrope axis of juvenile mice against the deleterious effects of unfavorable metabolic conditions
Poor metabolic conditions inhibit the neuroendocrine gonadotrope axis in mammals. In the present study, wild-type mice in the food restriction group experienced the expected delay at the onset of puberty compared with their controls (Fig. 1 ). In sharp contrast, all Y1-deficient mice subjected to the same degree of food restriction achieved puberty before day 50 of age (Fig. 1) . Consistently, their plasma LH levels on the day of death (Fig. 1 , insert) as well as uterus weight, a reliable index of circulating estrogen levels, were identical to those of the normally fed, postpubertal controls. This was also in contrast to data obtained in wild-type animals, where mice in the food restriction group had significantly lower circulating LH levels and uterus weights than controls at the end of the experiment.

View larger version (15K): [in this window] [in a new window]   Figure 1. Timing of puberty as illustrated by the number of animals (percent) with vaginal opening throughout the experiment. Top panel: wild-type animals; bottom panel: Y1 knockouts. Inserts display the levels of circulating LH at day 50 in both groups (means±SE). *P < 0.05 vs. ad lib fed mice of same strain.

CONCLUSION AND SIGNIFICANCE

In basal conditions, prepubertal Y1-deficient mice exhibit defective weight gain despite a feeding pattern similar (at least after weaning) to that of wild-type controls. This observation confirms the phenotype of adult Y1-deficient mice that eat normally. However, adult knockout mice become obese because of an exaggerated accumulation of fat. Our results on body weight gain of juvenile animals now suggest that fat accumulation in Y1 knockouts does not start before puberty, implying a participation of gonadal steroid hormones to this metabolic defect. This is corroborated by the increase in circulating leptin levels measured at day 50 in ad lib fed Y1 knockouts, demonstrating that a pathological increase in fat storage has begun by the end of puberty.

Unfavorable metabolic conditions down-regulate the gonadotrope axis in mammals, an effect at least partially mediated by hypothalamic NPY. Indeed, acute fasting is associated with increases in hypothalamic NPY expression in a variety of species. In this study, we found that hypothalamic NPY mRNA levels were increased in both strains after 2 wk of moderate feeding restriction. This observation indicates that variations in NPY expression also contribute to the modulation of hypothalamic function according to less extreme metabolic changes.

Consistently, this moderate feeding restriction induced the expected delay in the onset of puberty of juvenile wild-type female mice exemplified by the absence of vaginal opening in the vast majority of animals. The experiment yielded markedly different results in mice deficient in the expression of Y1: all knockout mice in the food restriction group achieved puberty within the duration of the experiment despite a slight delay in their age at vaginal opening compared with the fed controls. As a result and in sharp contrast to wild-type animals, their plasma LH levels and the weight of their uterus on day 50 of age were in the adult range and identical to those of the normally fed controls.

Food restriction induced a similar degree of growth retardation in Y1^-/- and wild-type mice. This implies that Y1^-/-mice with limited access to food could achieve puberty despite a deficit in body weight that was incompatible with normal pubertal development in more than 80% of wild-type animals. Furthermore, puberty occurred in Y1^-/- mice subjected to food restriction in spite of a decrease in peripheral circulating leptin levels as well as an increase in hypothalamic NPY expression. These observations indicate that in the absence of Y1, the gonadotrope axis appeared insensitive to these signals of decreasing energy stores, demonstrating a physiological role for Y1 in the sensing of endogenous metabolic parameters by the hypothalamus.

In conclusion, we have demonstrated that a lack of Y1 markedly impairs the sensing of unfavorable metabolic conditions by the neuroendocrine reproductive axis. This observation implicates Y1 in the mediation of the effects of increases in hypothalamic NPY on the gonadotrope axis. Based on the present results and previous data obtained in the same knockout model, we propose that Y1 is an important, if not the major, NPY receptor involved in this effect.

View larger version (28K): [in this window] [in a new window]   Figure 2. Schematic diagram. The top panels (A1 and A2) illustrate the normal function of the leptin-NPY-GnRH pathway in situations of normal caloric intake (A1) and in food restriction (A2). When animals are allowed ad libitum feeding, physiologic leptin levels in the periphery inhibit the expression of hypothalamic NPY (A1). Consequently, there is a decrease in NPY-mediated tonic inhibition of GnRH neurons, which therefore can activate the gonadotrope axis. When circulating leptin levels decrease, hypothalamic NPY expression increases, thus inhibiting the activity of GnRH neurons (A2). The bottom panels (B1 and B2) illustrate the function of this pathway in the absence of Y1. Deletion of Y1 has no effect on gonadotrope axis activation in situations of normal leptin and low NPY expression (B1). However, when Y1 is deleted, the inhibition exerted by high endogenous NPY expression cannot be conveyed on GnRH neurons, resulting in normal activation of the gonadotrope axis observed in our experiments (B2).

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0189fje

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