| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online March 12, 2002 as doi:10.1096/fj.01-0754fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Division of Endocrinology, Diabetology and Metabolism, and
* Division of Hypertension, University of Lausanne Medical School. CH-1011 Lausanne, Switzerland;
Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA; and
Department of Physiology, Faculty of Medicine, 1211 Geneva 4, Switzerland
2Correspondence: BH 19–707, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland. E-mail: Francois.Pralong{at}chuv.hospvd.ch
SPECIFIC AIMS
We studied the functional importance of the NPY Y1 and Y5 receptors located downstream of leptin actions in controlling energy homeostasis and reproduction. The feeding response and activity of the gonadotrope axis were evaluated in various situations in which the circulating levels of leptin varied from no leptin (ob/ob mice) to low leptin levels (fasting), and finally to high leptin concentrations (leptin injections). Experiments were performed in mice deficient for either of the two NPY receptor subtypes and in NPY Y1-deficient mice carrying a nonfunctional leptin gene (ob/ob mice).
PRINCIPAL FINDINGS
1. Mice deficient for NPY Y1 receptor expression have the same sensitivity to the anorexigenic actions of leptin as normal wild-type mice
Because leptin and NPY have opposite effects on hypothalamic regulation of energy metabolism, we first investigated whether leptin signaling could be facilitated in mice lacking NPY Y1 receptors. NPY Y1 knockouts and wild-type controls received either three leptin injections per day or PBS for 2 days. Leptin induced marked reductions in food intake and body weight in both wild-type mice and mice lacking the NPY Y1 receptor. The extent of the leptin effects was similar in both groups.
2. The acceleration of puberty by leptin is largely facilitated in mice deficient for NPY Y1 receptor expression
Leptin was reported to modulate the onset of puberty, probably in part by inhibiting hypothalamic NPY expression. Therefore, the importance of the NPY Y1 and Y5 receptor subtypes in mediating the NPY pathways involved in the control of puberty was assessed. First, the timing of spontaneous puberty was found to be similar in all groups (Y1 and Y5 knockouts, wild type controls). Then, juvenile mice were treated with daily injections of leptin. A marked advancement of puberty was observed in leptin-treated NPY Y1 receptor knockouts (Fig. 1
) independent of a change in body weight. Statistical analysis demonstrated the higher sensitivity to leptin of the gonadotrope axis of Y1-/- mice by disclosing a significant interaction between genotype and treatment (P<0.05, two-way ANOVA). In contrast, puberty in mice lacking the NPY Y5 receptor subtype was not affected by leptin treatment (Fig. 1)
.
|
3. Inhibition of the gonadotrope axis in response to fasting (low leptin levels) is attenuated in mice deficient for NPY Y1 receptor expression
Fasting inhibits the reproductive axis, most likely via an increase in hypothalamic NPY expression. Therefore, the respective roles of the Y1 and Y5 receptors in mediating this inhibition were investigated in fasted adult male mice. Pituitary LH contents and the weights of seminal vesicles were measured to evaluate reproductive function. At the end of the fasting period, significant reductions in the weight of seminal vesicles observed in all groups demonstrated the inhibition expected. However, in fasted mice lacking the Y1 receptor, pituitary LH content and the weight of seminal vesicles were higher than in fasted wild-type controls, suggesting resistance to the effects of starvation.
4. Hyperphagia and inhibition of the gonadotrope axis in leptin-deficient mice are attenuated by removal of the NPY Y1 receptor alleles
To further investigate the role of the NPY Y1 receptor subtype in modulating the effects of leptin on metabolism and reproductive function, we produced leptin-deficient mice harboring an inactivating mutation in the NPY Y1 gene by crossing Y1-/- and ob/ob mice. We first measured food intake and body weight change in mice between 1 wk after weaning up to 7 wk of age. Hyperphagia was significantly reduced in ob/ob mice bearing a null mutation at the Y1 alleles. Consequently, leptin-deficient animals bearing the Y1 mutation displayed a modest but significant reduction in body weight compared with their obese controls (Fig. 2
).
|
The effect of the NPY Y1 receptor deletionon the gonadotrope axis was next evaluated in adult male mice. As anticipated, pituitary LH content and seminal vesicle weights were significantly reduced in ob/ob mice. In contrast, these markers of reproductive axis activity were restored to normal in ob/ob mice lacking the NPY Y1 receptor.
CONCLUSION AND SIGNIFICANCE
The present study demonstrates that activation of the leptin pathways controlling feeding behavior is independent of the presence of a functional NPY Y1 receptor since leptin injection induces similar reductions of feeding in Y1 knockouts and wild-types. This is comparable to mice lacking the Y5 receptor, in which the anorexigenic effects of leptin were previously reported unchanged. Conversely, leptin deficiency results in hyperphagia that depends partially on a chronic stimulation of the NPY Y1 receptor as suggested by the reduction of food intake observed in ob/ob mice lacking Y1. This is in contrast to what was reported for mutant mice lacking leptin and functional NPY Y5 genes, in which hyperphagia was not altered by Y5 deficiency. Our data, therefore, confirm the crucial importance of the NPY Y1 receptor in controlling feeding in stimulated conditions, i.e., when hypothalamic NPY expression is activated.
Low energy intake is associated with an inhibition of the gonadotrope axis that is mediated partially by increased hypothalamic NPY expression. Y1 and Y5 have been implicated in this effect. In contrast, leptin was shown to restore gonadotrope function during unfavorable metabolic conditions and to advance spontaneous pubertal development in normal mice. The present data demonstrate that the efficacy of leptin to accelerate puberty is dramatically increased in the absence of Y1, indicating that the Y1 receptor plays a major role in a leptin-NPY-GnRH pathway.
We also assessed the activity of the gonadotrope axis in mice lacking NPY receptors in a state of low leptin levels (fasting) and in the absence of leptin (ob/ob mice), situations of high hypothalamic NPY expression. Starvation led to inhibition of the gonadotrope axis in all groups, suggesting that deficiency of a single NPY receptor subtype is not by itself sufficient to attenuate the detrimental effects of fasting. However, mice lacking Y1 show some degree of resistance to starvation not observed in Y5 knockouts, further suggesting the involvement of Y1 in modulating reproductive functions. The higher resistance to fasting of the gonadotrope axis in Y1-/- mice is accompanied by elevated circulating leptin levels that may facilitate leptin pathways in a manner similar to controlling the onset of puberty. A correction of the hypogonadism is also observed in ob/ob mice lacking Y1. In this case, a role of leptin can be excluded. Therefore, these results suggest that in Y1 knockouts, the blockade of leptin-independent NPY pathways implicating Y1 contribute to the beneficial effects on the gonadotrope axis.
Our data demonstrate that the NPY pathways controlling either feeding behavior or reproductive function are mediated by the NPY Y1 receptor. In contrast, our data and results obtained by others using ob/ob mice lacking the Y5 receptor do not support an important role for the NPY Y5 receptor in mediating these NPY effects. Nevertheless, the results do not rule out the possible involvement of either the Y5 or another NPY receptor subtype. The NPY Y1 subtype appears to modulate leptin actions in situations of high hypothalamic NPY expression. However, leptin-independent pathways involving Y1 must also exist to control feeding and activity of the reproductive axis, since an effect of the Y1 mutation can be observed in ob/ob mice. It is therefore tempting to speculate the existence of two different NPY Y1-mediated pathways modulating feeding and reproduction.
|
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0754fje; to cite this article, use FASEB J. (March 12, 2002) 10.1096/fj.01-0754fje 
This article has been cited by other articles:
|
|
 |
|
  M. M. Kamiji and A. Inui Neuropeptide Y Receptor Selective Ligands in the Treatment of Obesity Endocr. Rev., October 1, 2007; 28(6): 664 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Baldock, S. J. Allison, P. Lundberg, N. J. Lee, K. Slack, E.-J. D. Lin, R. F. Enriquez, M. M. McDonald, L. Zhang, M. J. During, et al. Novel Role of Y1 Receptors in the Coordinated Regulation of Bone and Energy Homeostasis J. Biol. Chem., June 29, 2007; 282(26): 19092 - 19102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Salvi, E. Castillo, M.-J. Voirol, M. Glauser, J.-P. Rey, R. C. Gaillard, P. Vollenweider, and F. P. Pralong Gonadotropin-Releasing Hormone-Expressing Neurons Immortalized Conditionally Are Activated by Insulin: Implication of the Mitogen-Activated Protein Kinase Pathway Endocrinology, February 1, 2006; 147(2): 816 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Sainsbury, H. T. Bergen, D. Boey, D. Bamming, G. J. Cooney, S. Lin, M. Couzens, N. Stroth, N. J. Lee, D. Lindner, et al. Y2Y4 Receptor Double Knockout Protects Against Obesity Due to a High-Fat Diet or Y1 Receptor Deficiency in Mice Diabetes, January 1, 2006; 55(1): 19 - 26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Blom, A. Stafleu, C. de Graaf, F. J Kok, G. Schaafsma, and H. F. Hendriks Ghrelin response to carbohydrate-enriched breakfast is related to insulin Am. J. Clinical Nutrition, February 1, 2005; 81(2): 367 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Vulliemoz, E. Xiao, L. Xia-Zhang, S. L. Wardlaw, and M. Ferin Central Infusion of Agouti-Related Peptide Suppresses Pulsatile Luteinizing Hormone Release in the Ovariectomized Rhesus Monkey Endocrinology, February 1, 2005; 146(2): 784 - 789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Coppola, B. A. Horwitz, J. Hamilton, and R. B. McDonald Expression of NPY Y1 and Y5 receptors in the hypothalamic paraventricular nucleus of aged Fischer 344 rats Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2004; 287(1): R69 - R75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Cunningham, M. Shahab, K. L. Grove, J. M. Scarlett, T. M. Plant, J. L. Cameron, M. S. Smith, D. K. Clifton, and R. A. Steiner Galanin-Like Peptide as a Possible Link between Metabolism and Reproduction in the Macaque J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1760 - 1766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. El-Haddad, M. Desai, D. Gayle, and M. G. Ross In Utero Development of Fetal Thirst and Appetite: Potential for Programming Reproductive Sciences, April 1, 2004; 11(3): 123 - 130. [Abstract] [PDF]
|
|
|
|
|
|
F. Maekawa, H.-M. A. Quah, K. Tanaka, and H. Ohki-Hamazaki Leptin Resistance and Enhancement of Feeding Facilitation by Melanin-Concentrating Hormone in Mice Lacking Bombesin Receptor Subtype-3 Diabetes, March 1, 2004; 53(3): 570 - 576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Sullivan and S. M. Moenter {gamma}-Aminobutyric Acid Neurons Integrate and Rapidly Transmit Permissive and Inhibitory Metabolic Cues to Gonadotropin-Releasing Hormone Neurons Endocrinology, March 1, 2004; 145(3): 1194 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. D. Raposinho, T. Pedrazzini, R. B. White, R. D. Palmiter, and M. L. Aubert Chronic Neuropeptide Y Infusion into the Lateral Ventricle Induces Sustained Feeding and Obesity in Mice Lacking Either Npy1r or Npy5r Expression Endocrinology, January 1, 2004; 145(1): 304 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Burcelin, B. Thorens, M. Glauser, R. C. Gaillard, and F. P. Pralong Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin Endocrinology, October 1, 2003; 144(10): 4484 - 4491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Hill and J. E. Levine Abnormal Response of the Neuropeptide Y-Deficient Mouse Reproductive Axis to Food Deprivation But Not Lactation Endocrinology, May 1, 2003; 144(5): 1780 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Sainsbury, C. Schwarzer, M. Couzens, and H. Herzog Y2 Receptor Deletion Attenuates the Type 2 Diabetic Syndrome of ob/ob Mice Diabetes, December 1, 2002; 51(12): 3420 - 3427. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
