Y 4 receptor knockout rescues fertility in ob / ob mice

Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4−/−) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4−/−,ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4−/− and Y4−/−,ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4−/− and Y4−/−,ob/ob animals. Y4−/− mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPYergic tonus.

[1]  G. Thomas,et al.  Hypothalamic Y2 receptors regulate bone formation. , 2002, The Journal of clinical investigation.

[2]  A. Isidori,et al.  Leptin in reproduction , 2001, Trends in Endocrinology & Metabolism.

[3]  A. Hayward,et al.  Stimulation of the Gonadotropic Axis by the Neuropeptide Y Receptor Y1 Antagonist/ Y4 Agonist 1229U91 in the Male Rat , 2000, Neuroendocrinology.

[4]  J. Wilding,et al.  Hypothalamic neuropeptide Y and its neuroendocrine regulation by leptin. , 2000, Frontiers of hormone research.

[5]  上野 尚彦.  Decreased food intake and body weight in pancreatic polypeptide-overexpressing mice , 2000 .

[6]  P. J. Larsen,et al.  Central Y4 receptor distribution. Radioactive ribonucleotide probe in situ hybridization with in vitro receptor autoradiography. , 2000, Methods in molecular biology.

[7]  D. Gehlert.  Role of hypothalamic neuropeptide Y in feeding and obesity , 1999, Neuropeptides.

[8]  H. Herzog,et al.  Regional distribution of Y‐receptor subtype mRNAs in rat brain , 1999, The European journal of neuroscience.

[9]  P S Kalra,et al.  Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. , 1999, Endocrine reviews.

[10]  K. Mounzih,et al.  Effect of the genetic background on the reproduction of leptin-deficient obese mice. , 1999, Endocrinology.

[11]  R. Krysiak,et al.  Interactions between the neuropeptide Y system and the hypothalamic-pituitary-adrenal axis. , 1999, European journal of endocrinology.

[12]  S. Kalra,et al.  Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y Y1 and Y4 receptors. , 1999, Endocrinology.

[13]  D. Smiley,et al.  The Neuropeptide Y Y1 Antagonist, 1229U91, A Potent Agonist for the Human Pancreatic Polypeptide-Preferring (NPY Y4) Receptor , 1998, Peptides.

[14]  F. Talamantes,et al.  Galanin regulates prolactin release and lactotroph proliferation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  E. Arenas,et al.  Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system , 1998, Neuroscience.

[16]  F. Pralong,et al.  Metabolic control of sexual function and growth: Role of neuropeptide Y and leptin , 1998, Molecular and Cellular Endocrinology.

[17]  T. Hökfelt,et al.  Neuropeptide Y: some viewpoints on a multifaceted peptide in the normal and diseased nervous system 1 Published on the World Wide Web on 4 December 1997. 1 , 1998, Brain Research Reviews.

[18]  G. Sperk,et al.  GABAA receptor subunits in the rat hippocampus III: altered messenger RNA expression in kainic acid-induced epilepsy , 1997, Neuroscience.

[19]  A. Blomqvist,et al.  Y-receptor subtypes—how many more? , 1997, Trends in Neurosciences.

[20]  K. Mounzih,et al.  Leptin treatment rescues the sterility of genetically obese ob/ob males. , 1997, Endocrinology.

[21]  D. McTigue,et al.  Effect of pancreatic polypeptide on rat dorsal vagal complex neurons. , 1997, The Journal of physiology.

[22]  L. Hennighausen,et al.  Stat5a is mandatory for adult mammary gland development and lactogenesis. , 1997, Genes & development.

[23]  P. Kelly,et al.  Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. , 1997, Genes & development.

[24]  R. Palmiter,et al.  Attenuation of the Obesity Syndrome of ob/ob Mice by the Loss of Neuropeptide Y , 1996, Science.

[25]  S. Woods,et al.  Specificity of Leptin Action on Elevated Blood Glucose Levels and Hypothalamic Neuropeptide Y Gene Expression in ob/ob Mice , 1996, Diabetes.

[26]  F. Chehab,et al.  Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin , 1996, Nature Genetics.

[27]  J. Levine,et al.  Steroid modulation of neuropeptide Y-induced luteinizing hormone releasing hormone release from median eminence fragments from male rats. , 1996, Neuroendocrinology.

[28]  M. Aubert,et al.  Chronic administration of neuropeptide Y into the lateral ventricle inhibits both the pituitary-testicular axis and growth hormone and insulin-like growth factor I secretion in intact adult male rats. , 1996, Endocrinology.

[29]  D. Larhammar,et al.  Cloning of a Human Receptor of the NPY Receptor Family with High Affinity for Pancreatic Polypeptide and Peptide YY (*) , 1995, The Journal of Biological Chemistry.

[30]  T. Branchek,et al.  Cloning and Functional Expression of a Human Y4 Subtype Receptor for Pancreatic Polypeptide, Neuropeptide Y, and Peptide YY (*) , 1995, The Journal of Biological Chemistry.

[31]  J. Bue-Valleskey,et al.  The role of neuropeptide Y in the antiobesity action of the obese gene product , 1995, Nature.

[32]  K. Rajewsky,et al.  A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. , 1995, Nucleic acids research.

[33]  C. Léránth,et al.  Role of neuropeptide-Y in episodic luteinizing hormone release in ovariectomized rats: an excitatory component and opioid involvement. , 1993, Endocrinology.

[34]  J. Stern,et al.  Autonomic control of pancreatic polypeptide and glucagon secretion during neuroglucopenia and hypoglycemia in mice. , 1993, The American journal of physiology.

[35]  S. Mccann,et al.  Effects of neuropeptide Y on gonadotropin and prolactin release in normal, castrated or flutamide-treated male rats. , 1993, Neuroendocrinology.

[36]  J. Mcdonald,et al.  Investigation of the effects of progesterone on neuropeptide Y-stimulated luteinizing hormone-releasing hormone secretion from the median eminence of ovariectomized and estrogen-treated rats. , 1990, Neuroendocrinology.

[37]  W. Young.  In situ hybridization histochemical detection of neuropeptide mRNA using DNA and RNA probes. , 1989, Methods in enzymology.

[38]  S. Kalra,et al.  Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. , 1997, Endocrinology.

[39]  I. Taylor,et al.  Failure of pancreatic polypeptide release in congenitally obese mice. , 1984, Gastroenterology.

[40]  T. Schwartz.  Pancreatic polypeptide: a unique model for vagal control of endocrine systems. , 1983, Journal of the autonomic nervous system.

[41]  I. Yamashita,et al.  Time course of hypothalamic CRF activity after the administration of two different stresses. , 1976, Endocrinologia japonica.