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Leptin, Growth and Reproduction

  • Conference paper
Brain Somatic Cross-Talk and the Central Control of Metabolism

Part of the book series: Research and Perspectives in Endocrine Interactions ((RPEI))

  • 89 Accesses

Summary

The elucidation of the ob/ob gene product, leptin, not only closed a gap in the understanding of the regulation of feeding but also offered a rationale for the humoral link between metabolic function and the regulation of hypothalamo-pituitary secretions. Absence of leptin production as seen in ob/ob mice or in some rare cases of human obesity not only leads to hyperphagia, reduced energy expenditure, and hypercorticism, but also, most importantly, to sterility. Partial or total leptin resistance by mutation of the leptin receptor leads to a similar phenotype, as seen in db/db mice, fa/fa Zucker rats and again in rare cases of human obesity. Common human obesity is characterized by partial resistance to clearly elevated circulating leptin levels. A key finding was the demonstration that treatment of sterile ob/ob mice with leptin could quickly restore fertility, implying that a minimum level of circulating leptin is necessary for positive stimulation of the gonadotropic axis, at least as a permissive factor. A similar situation was seen with the treatment of two patients with leptin deficiency. Furthermore, leptin was shown to modulate other hypothalamo-pituitary axes. A general finding has been that leptin administration to animals undergoing severe reduction in energetic supply could reverse the negative effects of such a metabolic insult on most endocrine axes, with striking effects on pulsatile growth hormone (GH) and LH secretions in the rat. Ingestive behavior is controlled by multiple interacting neuroendocrine circuits that are leptin-dependent, involving neuropeptides such as Neuropeptide Y (NPY), Melanocortins (MCs), AGRP, CART, GLP-1, Orexin, etc. Generally speaking, a deficit in feeding corresponds to centrally induced reduction in sexual function. NPY is primarily known to stimulate feeding but also to modulate sexual behavior and gonadotropin secretion. Apparently reproductive function is not dependent on hypothalamic α-MSH or CART action. The recently described natural ligand of the GHRP receptor, ghrelin, which is synthesized and release by the stomach, not only stimulates GH secretion, as predicted, but also regulates feeding by acting on hypothalamic neuropeptides such as NPY. Ghrelin action seems to represent a counterbalance of leptin action. Whereas leptin decreases feeding and can produce anorexia, ghrelin stimulates feeding and eventu- ally produces obesity. Thus a trend for coordinated neuroendocrine regulation of ingestive and reproductive behavior in response to metabolic and environmental changes is expected, with a clear integrative role for leptin and possibly insulin. Still, much remains to be learned about the mode of action of leptin to activate GnRH secretion and reproduction in mammals.

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References

  • Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS (1996) Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252

    Article  PubMed  CAS  Google Scholar 

  • Ahima RS, Dushay J, Flier SN, Prabakaram D, Flier JS (1997) Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 99:391–395

    Article  PubMed  CAS  Google Scholar 

  • Asnicar MA, Smith DP, Yang DD, Heiman ML, Fox N, Chen YF, Hsiung HM, Köster A (2001) Absence of Cocaine-and Amphetamine-Regulated Transcript in obesity in mice fed a high calorie diet. Endocrinology 142:4394–4400

    Article  PubMed  CAS  Google Scholar 

  • Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau J-P, Bortoluzzi M-N, Moizo L, Lehy T, Guerre-Millo, Le Marchand-Brustel Y, Lewin MJM (1998) The stomach is a source of leptin. Nature 394:790–794

    Article  PubMed  CAS  Google Scholar 

  • Bagnasco M, Kalra PA, Kalra SP (2002) Ghrelin and leptin pulse discharge in fed and fasted rats. Endocrinology 143:726–729

    Article  PubMed  CAS  Google Scholar 

  • Barash IA, Cheung CC, Weigle DS, Ren H, Kabitting EB, Kuijer JL, Clifton DK, Steiner RA (1996) Leptin is a metabolic signal to the reproductive system. Endocrinology 137:3144–3147

    Article  PubMed  CAS  Google Scholar 

  • Baskin DG, Lattemann DF, Seeley RJ, Woods SC, Porte D Jr, Schwartz MW (1999) Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res 848:114–123

    Article  PubMed  CAS  Google Scholar 

  • Becker DJ, Ongemba LN, Brichard V, Henquin JC, Brichard SM (1995) Diet-and diabetes-induced changes of ob gene expression in rat adipose tissue. FEBS Letters 371:324–328

    Article  PubMed  CAS  Google Scholar 

  • Blum WF, Englaro P, Hanitsch S, Jull A, Hertel NT, Müller J, Skakkebaek NE, Heiman ML, Birkett M, Attanasio A, Kiess W, Rascher W (1997) Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, pubertal stage, and testosterone. J Clin Endocrinol Metab 82:2904–2910

    Article  PubMed  CAS  Google Scholar 

  • Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang K (1980) Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 106:663–667

    Article  PubMed  CAS  Google Scholar 

  • Bronson FH (1986) Food-restricted, prepubertal female rats: rapid recovery of luteinizing hormone pulsing with excess food and full recovery of pubertal development with gonadotropin-releasing hormone. Endocrinology 118:2483–2487

    Article  PubMed  CAS  Google Scholar 

  • Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban DJ, Klein R, Krone W, Müller-Wieland D, Kahn CR (2000) Role of brain insulin receptor in control of body weight and reproduction. Science 289:2212–2125.

    Article  Google Scholar 

  • Bucholtz DC, Vidwans NM, Herbosa CG, Schillo KK, Foster DL (1996) Metabolic interfaces between growth and reproduction V. Pulsatile LH secretion is dependent upon glucose availability. Endocrinology 137:601–607

    Article  PubMed  CAS  Google Scholar 

  • Caprio M, Isidori AM, Carta AR, Moretti C, Dufau ML, Fabbri A (1999) Expression of functional leptin receptors in rodents Leydig cells. Endocrinology 140:4939–4947

    Article  PubMed  CAS  Google Scholar 

  • Carro E, Pinilla L, Seoane LM, Considine RV, Aguilar E, Casanueva FF, Dieguez C (1997a) Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats. Neuroendocrinology 66:375–377

    Article  PubMed  CAS  Google Scholar 

  • Carro E, Señaris R, Considine RV, Casanueva FF, Dieguez C (1997b) Regulation of in vivo growth hormone secretion by leptin. Endocrinology 138:2203–2206

    Article  PubMed  CAS  Google Scholar 

  • Carro E, Señaris RM, Seoane LM, Frohman LA, Arimura A, Casanueva FF, Dieguez C (1999) Role of growth hormone (GH)-releasing hormone and somatostatin on leptin-induced GH secretion. Neuroendocrinology 69:3–10

    Article  PubMed  CAS  Google Scholar 

  • Catzeflis C, Pierroz DD, Rohner-Jeanrenaud F, Rivier J, Sizonenko PC, Aubert ML (1993) Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats. Endocrinology 132:224–234

    Article  PubMed  CAS  Google Scholar 

  • Chehab FF, Mounzih K, Lu R, Lim ME (1996) Early onset of reproductive function in normal mice treated with leptin. Science 275:88–90

    Article  Google Scholar 

  • Chehab F, Lim M, Lu R (1997) Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nature Genet 12:318–320

    Article  Google Scholar 

  • Cheung CC, Thornton JE, Kuijper JL, Weigle DS, Clifton DK, Steiner RA (1996) Leptin is a metabolic gate for the onset of puberty in the female rat. Endocrinology 138:855–858

    Article  Google Scholar 

  • Cioffi JA, Van Blerkom J, Antczak M, Shafer A, Wittmer S, Snodgrass HR (1997) The expression of leptin and its receptors in the pre-ovulatory human follicles. Mol Human Reprod 3:467–472

    Article  CAS  Google Scholar 

  • Clement K, Vausse C, Lahalo N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P & GuyGrand B (1998) A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401

    Article  PubMed  CAS  Google Scholar 

  • Cone RD (1999) The central melanocortin system and energy homeostasis. Trends Endocrinol Metab 10:211–216

    Article  PubMed  CAS  Google Scholar 

  • Cunningham MJ, Clifton DK, Steiner RA (1999) Leptin’s action on the reproductive axis: perspectives and mechanisms. Biol Reprod 60:216–222

    Article  PubMed  CAS  Google Scholar 

  • Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K, Sakurai T, Yanagisawa M, Nakazato M (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753.

    Article  PubMed  CAS  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2nd, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327

    Article  PubMed  Google Scholar 

  • Dieterich KD, Lehnert H (1998) Expression of leptin receptor mRNA and the long form splice variant in human pituitary and pituitary adenoma. Exp Clin Endocrinol Diabetes 106:522–525

    Article  PubMed  CAS  Google Scholar 

  • Distiller LA, Sagel J, Morley JE, Joffe BI, Seftel HC (1975) Pituitary responsiveness to luteinizing hormone-releasing hormone in insulin-dependent diabetes mellitus. Diabetes 24:378–380

    Article  PubMed  CAS  Google Scholar 

  • El Majdoubi M, Sahu A, Ramaswamy, Plant TM (2000) Neuropeptide Y: a hypothalamic brake restraining the onset of puberty in primates. Proc Natl Acad Sci USA 97:6179–6184

    Article  Google Scholar 

  • Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB (1998) Distribution of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol 395:535–547

    Article  PubMed  CAS  Google Scholar 

  • Fan W, Boston BA, Kesterson RA, Hruby, VJ, Cone RD (1997) Role of melanocortinergic neurons in feeding and the Agouti obesity syndrome. Nature 385:165–168

    Article  PubMed  CAS  Google Scholar 

  • Farooqi IS (2002) Leptin and the onset of puberty: insights from rodent and human genetics. Semin Reprod Med 20:139–144

    Article  PubMed  CAS  Google Scholar 

  • Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884

    Article  PubMed  CAS  Google Scholar 

  • Farooqi IS, Yeo GSH, Keogh JM, Aminian S, Jebb SA, Butler G, Cheetham T, O’Rahilly S (2000) Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J Clin Invest 106:271–279

    Article  PubMed  CAS  Google Scholar 

  • Foster DL, Bucholtz DC, Herbosa CG (1995) Metabolic signals and the timing of puberty in sheep. In: Plant TM and Lee PA (eds) The neurobiology of puberty. Bristol, UK, J Endocrinol, pp. 243–257

    Google Scholar 

  • Foster DL, Nagatani S (1999) Physiological perspectives on leptin as a regulator of reproduction: role in timing puberty. Biol Reprod 60:205–215

    Article  PubMed  CAS  Google Scholar 

  • Frisch RE (1980) Pubertal adipose tissue: is it necessary for normal sexual maturation?. Fed Proc 39:2395–2400

    PubMed  CAS  Google Scholar 

  • Gehlert DR (1998) Multiple receptors for the pancreatic polypeptide (PP-fold) family: physiological implications. Proc Soc Exper Biol Med 218:7–22

    CAS  Google Scholar 

  • Gruaz NM, Pierroz DD, Rohner-Jeanrenaud F, Sizonenko PC, Aubert ML (1993) Evidence that neuropeptide Y could represent a neuroendocrine inhibitor of sexual maturation in unfavorable metabolic conditions in the rat. Endocrinology 133:1891–1895

    Article  PubMed  CAS  Google Scholar 

  • Gruaz NM, Lalaoui M, Pierroz DD, Raposinho PD, Blum WF, Aubert ML (1998a) Failure of leptin administration to advance sexual maturation in the female rat. 80th Annual Meeting of the Endocrine Society. New Orleans, Louisiana, Abstract P3–668

    Google Scholar 

  • Gruaz NM, Lalaoui M, Pierroz DD, Englaro P, Sizonenko PC, Blum WF, Aubert ML (1998b) Chronic administration of leptin into the lateral ventricle induces sexual maturation in severely food-restricted female rats. J Neuroendocrinol 10:627–633

    Article  PubMed  CAS  Google Scholar 

  • Guillemin R, Brazeau P, Bohlen P, Esch F, Ling N, Wehrenberg WB (1982) Growth hormone-releasing factor from a human pancreatic caused acromegaly. Science 218:585–587

    Article  PubMed  CAS  Google Scholar 

  • Hakansson M, de Lecea L, Sutcliffe JG, Yanagisawa M, Meister B (1999) Leptin receptor-and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus. J Neuroendocrinol 11:653–663

    Article  PubMed  CAS  Google Scholar 

  • Havel PJ, Uriu-Hare Y, Liu T, Stanhope KL, Stern JS, Keen CL, Ahren B (1998) Marked and rapid decreases of circulating leptin in Streptozotocin diabetic rats: reversal by insulin. Am J Physiol 274:R1482–R1491

    PubMed  CAS  Google Scholar 

  • Hohmann JG, Teal TH, Clifton DK, Davis J, Hruby VJ, Han G, Steiner RA (2000) Differential role of Melanocortin in mediating leptin’s central effects on feeding and reproduction. Am J Physiol 278:R50–R59

    CAS  Google Scholar 

  • Horvarth TL, Diano S, Sotonyi P, Heiman M, Tschop M (2001) Minireview: ghrelin and the regulation of energy balance-a hypothalamic perspective. Endocrinology 142:4163–4169

    Article  Google Scholar 

  • Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH, (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977

    Article  PubMed  CAS  Google Scholar 

  • Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F(1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141

    Article  PubMed  CAS  Google Scholar 

  • Iqbal J, Pompolo S, Considine RV, Clarke IJ (2000) Localization of leptin receptor-like immunoreactivity in the corticotropes, somatotropes, and gonadotropes in the ovine anterior pituitary. Endocrinology 141:1515–1520

    Article  PubMed  CAS  Google Scholar 

  • Iqbal J, Pompolo S, Sakurai T, Clarke IJ (2001) Evidence that Orexin-containing neurons provide direct input to Gonadotropin-Releasing Hormone neurons in the ovine hypothalamus. J Neuroendocrinol 13:1033–1041

    Article  PubMed  CAS  Google Scholar 

  • Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nature Rev 2:1–10

    Google Scholar 

  • Jain MR, Pu S, Kalra PS, Kalra SP (1999) Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed rats may involve neuropeptide Y Y1 and Y4 receptors. Endocrinology 140:5171–5177

    Article  PubMed  CAS  Google Scholar 

  • Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV (1999) Leptin and leptin receptor expression in normal and neoplastic human pituitary: evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 84:2903–2909

    Article  PubMed  CAS  Google Scholar 

  • Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV (2000) Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 141:333–339

    Article  PubMed  CAS  Google Scholar 

  • Kalra SP (1993) Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing-hormone-releasing hormone discharge. Endocrinol Rev 14:507–538

    CAS  Google Scholar 

  • Karlsson C, Lindell K, Svenssonh E, Bergh C, Lind P, Billig H, Carlsson LS, Carlsson B (1997) Expression of functional leptin receptors in the human ovary. J Clin Endocrinol Metab 82:4144–4148

    Article  PubMed  CAS  Google Scholar 

  • Kiess W, Blum WF, Aubert ML (1998) Leptin, puberty and reproductive function: lessons from animal studies and observations in humans. Eur J Endocrinol 138:26–29

    Article  PubMed  CAS  Google Scholar 

  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth hormone releasing acylated peptide from stomach. Nature 402:656–660

    Article  PubMed  CAS  Google Scholar 

  • Kristensen P, Judge ME, Thim L, Ribel U, Christ] ansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N, Larsen PJ, Hastrup S (1998) Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393:72–76

    Article  PubMed  CAS  Google Scholar 

  • Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai T (1999) Orexins/hypocretins regulate drinking behaviour. Brain Res 842:256–261

    Article  PubMed  CAS  Google Scholar 

  • Lebrethon MC, Vandersmissen E, Gérard A, Parent AS, Junien JL, Bourguignon J-P (2000a) In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms. Endocrinology 141:1464–1469

    Article  PubMed  CAS  Google Scholar 

  • Lebrethon MC, Gérard A, Parent AS, Bourguignon JP (2000b) Cocaine and amphetamine-regulated transcript peptide mediation of leptin stimulatory effect on the rat gonadotropinreleasing hormone pulse generator in vitro. J of Neuroendocrinology 12:383–386

    Article  CAS  Google Scholar 

  • Li C, Chen P, Smith MS (1999) Identification of neuronal input to the arcuate nucleus (ARH) activated during lactation: implications in the activation of neuropeptide Y neurons. Brain Res 824:267–276

    Article  PubMed  CAS  Google Scholar 

  • Lopez M, Seoane L, Garcia MC, Lago F, Casanueva FF, Señaris R, Dieguez C (2000) Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. Biochem Biophys Res Commun 269:41–45

    Article  PubMed  CAS  Google Scholar 

  • Magni P, Vettor R, Pagano C, Calcagno A, Beretta E, Mesdsi E, Zanisi M, Martini L, Motta M (1999) Expression of a leptin receptor in immortalized gonadotropin-releasing hormone-secreting neurons. Endocrinology 140:1581–1585

    Article  PubMed  CAS  Google Scholar 

  • Mantzoros CS, Flier JS, Rogol AD (1997) A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab 82:1066–1070

    Article  PubMed  CAS  Google Scholar 

  • Marsh DJ, Hollopeter G, Kafer KE, Palmiter RD (1998) Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nature Med 4:718–721

    Article  PubMed  CAS  Google Scholar 

  • Masuzaki H, Ogawa Y, Sagawa N, Hosofda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans. Nature Med 3:1029–1033

    Article  PubMed  CAS  Google Scholar 

  • Mercer JG, Hoggrad N, Williams LM, Lawrence CB, Hannah LT, Morgan PJ, Trayhurn P (1996) Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J of Neuroendocrinology 8:733–735

    Article  CAS  Google Scholar 

  • Morash B, Li A, Murphy PR, Wilkinson M, Ur E (1999) Leptin gene expression in the brain and pituitary gland. Endocrinology 140:5995–5998

    Article  PubMed  CAS  Google Scholar 

  • Moschos S, Chan JL, Mantzoros CS (2002) Leptin and reproduction: a review. Fertility and Sterility 77:433–444

    Article  PubMed  Google Scholar 

  • Mounzih K, Lu R, Chehab FF (1997) Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 138:1190–1193

    Article  PubMed  CAS  Google Scholar 

  • Nagatani S, Guthikonda P, Thompson RC, Tsukamura H, Maeda K-I, Foster DL (1998) Evidence for GnRH regulation by leptin: Leptin administration prevents reduced pulsatile LH secretion during fasting. Neuroendocrinology 67:370–376

    Article  PubMed  CAS  Google Scholar 

  • Ogawa Y, Masuzaki H, Hosoda K, Aizawa-Abe M, Suga J, Suga M, Ebihara K, Iwai H, Matsuoka N, Satoh N, Odaka H, Kasuga H, Fujisawa Y, Inoue G, Nishimura H, Yoshimasa Y, Nakao K. (1999) Increased glucose metabolism and insulin sensitivity in transgenic skinny mice over-expressing leptin. Diabetes 48:1822–1829

    Article  PubMed  CAS  Google Scholar 

  • Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135–138

    Article  PubMed  CAS  Google Scholar 

  • Pedrazzini T, Seydoux J, Kunstner P, Aubert JF, Grouzmann E, Beermann F, Brunner HR (1998) Cardiovascular response, feeding behavior and locomotor activity in mice lacking the NPY Y1 receptor. Nature Med 4:722–726

    Article  PubMed  CAS  Google Scholar 

  • Pierroz DD, Gruaz NM, d’Allèves V, Aubert ML (1995) Chronic administration of neuropeptide Y into the lateral ventricle starting at 30 days of life delays sexual maturation in the female rat. Neuroendocrinology 61:293–300

    Article  PubMed  CAS  Google Scholar 

  • Pierroz DD, Catzeflis C, Aebi AC, Rivier JE, Aubert ML (1996) 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. Endocrinology 137:3–12

    Article  PubMed  CAS  Google Scholar 

  • Pierroz DD, Héritier A, Lalaoui M, d’Allèves V, Blum WF, Aubert ML (1997) Leptin is a metabolic signal for sexual function: reciprocal changes in plasma leptin and arcuate nucleus NPY mRNA in two models of adverse metabolic conditions with hypogonadism. The Endocrine Society, 79th Annual Meeting, June 1997, Abstract OR24-6

    Google Scholar 

  • Pierroz DD, Gruaz-Gumowski NM, Lalaoui M, Blum WF, Aubert ML (2000) Leptin and NPY regulation of sexual maturation in the rat. In: Bourguignon JP and Plant TM (eds), the Onset of Puberty in Perspective. Elsevier, Amsterdam, pp 339–349

    Google Scholar 

  • Pierroz DD, Aebi A, Huhtaniemi IT, Aubert ML (1999b) Many LH peaks are needed to physiologically stimulate testosterone secretion: modulation by fasting and NPY. Am J Physiol 276:E603–E610

    PubMed  CAS  Google Scholar 

  • Plant TM, Durrant AR (1997) Circulating leptin does not appear to provide a signal for triggering the initiation of puberty in the male rhesus monkey (Macaca Mulatta). Endocrinology 138:4505–4508

    Article  PubMed  CAS  Google Scholar 

  • Pralong FP, Gonzales C, Voirol MJ, Palmiter RD, Brunner HR, Gaillard RC, Seydoux J, Pedrazzini T (2002) The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy home-ostasis and reproductive functions. FASEB J. 16:712–714

    PubMed  CAS  Google Scholar 

  • Pu S, Jain MR, Kalra PS, Kalra SP (1998) Orexins, a novel family of hypothalamic neuropeptides, modulate pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner. Regul Pept 78:133–136

    Article  PubMed  CAS  Google Scholar 

  • Quintela M, Señaris R, Heiman ML, Casanueva FF, Dieguez C (1997) Leptin inhibits in vitro hypothalamic somatostatin secretion and somatostatin mRNA levels. Endocrinology 138:5641–5644

    Article  PubMed  CAS  Google Scholar 

  • Raposinho PD, Broqua P, Pierroz DD, Hayward A, Dumont Y, Quirion R, Junien JL, Aubert ML (1999) Evidence that the inhibition of LH secretion exerted by central administration of Neuropeptide Y (NPY) in the rat is predominantly mediated by the NPY-Y5 receptor subtype. Endocrinology 140:4046–4055

    Article  PubMed  CAS  Google Scholar 

  • Raposinho PD, Broqua P, Hayward A, Akinsanya K, Galyean R, Schteingart C, Junien JL, Aubert ML (2000a) Stimulation of the gonadotropic axis by the neuropeptide Y receptor Y1 antagonist/Y4 agonist 1229U91 in the male rat. Neuroendocrinology 71:2–7

    Article  PubMed  CAS  Google Scholar 

  • Raposinho PD, Castillo E, d’Allèves V, Broqua P, Pralong FP, Aubert ML (2000b) Chronic blockade of the Melanocortin 4 receptor subtype leads to obesity independently of Neuropeptide Y action, with no adverse effects on the gonadotropic and somatotropic axes. Endocrinology 141:4419–4427

    Article  PubMed  CAS  Google Scholar 

  • Raposinho PD, Pierroz DD, Broqua P, White RW, Pedrazzini T, Aubert ML (2001) Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism. Mol Cellular Endocrinol 185:195–204

    Article  CAS  Google Scholar 

  • Rohner-Jeanrenaud F, Cusin I, Sainsbury A, Zakrzewska KE, Jeanrenaud B (1996) The loop system between Neuropeptide Y and leptin in normal and obese rodents. Horm Metab Res 28:642–648

    Article  PubMed  CAS  Google Scholar 

  • Russell SH, Kim MS, Small CJ, Abbott CR, Morgan DG, Taheri S, Murphy KG, Todd JF, Ghatei MA, Bloom SR (2000) Central administration of orexin A suppresses basal and domperidone stimulated plasma prolactin. J Neuroendocrinol 12:1213–1218

    Article  PubMed  CAS  Google Scholar 

  • Russell SH, Small CJ, Kennedy AR, Stanley SA, Seth A, Murphy KG, Taheri S, Ghatei MA, Bloom SR (2001) Orexin A interactions in the hypothalamo-pituitary gonadal axis. Endocrinology 142:5294–5302

    Article  PubMed  CAS  Google Scholar 

  • Sahu A, Sninsky CA, Phelps CP, Dube MG, Kalra PS, Kalra SP (1992) Neuropeptide-Y release from the paraventricular nucleus increases in association with hyperphagia in strepto-zotocin-induced diabetic rats. Endocrinology 131:2979–2985

    Article  PubMed  CAS  Google Scholar 

  • Sainsbury A, Schwartzer C, Couzens M, Jenkins A, Aokes SR, Ormandy CJ, Herzog H (2002) Y4 receptor knockout rescues fertility in ob/ob mice. Genes Dev 16:1077–1088

    Article  PubMed  CAS  Google Scholar 

  • Sakurai T (1999) Orexins and orexin receptors: implication in feeding behavior. Regul Pept 85:25–30

    Article  PubMed  CAS  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  PubMed  CAS  Google Scholar 

  • Schneider JE, Goodman MD, Tang S, Bean B, Ji H, Friedman MI (1998) Leptin indirectly affects estrous cycles by increasing metabolic fuel oxidation. Horm Behav 33:217–228

    Article  PubMed  CAS  Google Scholar 

  • Schwartz MW, Figlewicz, Baskin DG, Woods SC, Porte D Jr (1992) Insulin in the brain: A hormonal regulator of energy balance. Endocrinol Rev 13:387–414

    CAS  Google Scholar 

  • Schwartz MW, Baskin DG, Bukowski TR, Kuijper JL, Foster D, Lasser G, Prunkard DE, Porte Jr D, Woods SC, Seeley RJ, Weigle DS (1995) Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45:531–535

    Article  Google Scholar 

  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671

    PubMed  CAS  Google Scholar 

  • Shimon I, Yan X, Magoffin DA, Friedman TC, Melmed S (1998) Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab. 83:4059–4064

    Article  PubMed  CAS  Google Scholar 

  • Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kangawa K, Nakao K (2001) Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50:227–232

    Article  PubMed  CAS  Google Scholar 

  • Small CJ, Kim MS, Stanley SA, Mitchell JRD, Murphy K, Morgan DGA, Ghatei MA, Bloom SR (2001) Effects of chronic central nervous system administration of Agouti-related protein in pair-fed animals. Diabetes 50:248–254

    Article  PubMed  CAS  Google Scholar 

  • Smith-Kirwin SM, O’Connor DM, De Johnston J, Lancey ED (1998) Leptin expression in human mammary epithelial cells and breast milk. J Clin Endocrinol Metab 83:1810–1813

    Article  PubMed  CAS  Google Scholar 

  • Spicer LJ, Francisco CC (1998) Adipose obese gene product, leptin, inhibits bovine ovarian thecal cell steroidogenesis. Biol Reprod 58:207–212

    Article  PubMed  CAS  Google Scholar 

  • Steger RW (1990) Neuroendocrine and reproductive consequences of diabetes mellitus in the male. In: Shafrir E (ed) Frontiers in diabetes research. Lessons from animal diabetes III. Smith-Gordon, pp. 529–537

    Google Scholar 

  • Steiner RA (1996) Editorial: Lords and Ladies Leapin’ on leptin. Endocrinology 137:4533–4534

    Article  PubMed  CAS  Google Scholar 

  • Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hofmann J, Hsiung HM, Kriauciunas A, MacKellar W, Rosteck PR, Schoner B, Smith D, Tinsley FC, Zhang XY, Heiman M (1995) The role of Neuropeptide Y in the antiobesity action of the obese gene product. Nature 377:530–532

    Article  PubMed  CAS  Google Scholar 

  • Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD (1998) A leptin missense mutation associated with hypogonadism and morbid obesity. Nature Genet 18:213–215

    Article  PubMed  CAS  Google Scholar 

  • Tamura T, Irahara M, Tezuka M, Kiyokawa M, Aono T (1999) Orexins, orexigenic hypothalamic neuropeptides, suppress the pulsatile secretion of luteinizing hormone in ovariectomized female rats. Biochem Biophys Res Commun 264:759–762

    Article  PubMed  CAS  Google Scholar 

  • Tannenbaum GS, Gurd W, Lapointe M (1998) Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone. Endocrinology 139:3871–3875

    Article  PubMed  CAS  Google Scholar 

  • Tena-Sempere M, Pinilla L, Gonzalez LC, Dieguez C, Casanueva FF, Aguilar E (1999) Leptin inhibits testosterone secretion from adult rat testis in vitro. J Endocrinol 161:211–218

    Article  PubMed  CAS  Google Scholar 

  • Thornton JE, Cheung CC, Clifton DK, Steiner RA (1997) Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138:5063–5066

    Article  PubMed  CAS  Google Scholar 

  • Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71–75

    Article  PubMed  CAS  Google Scholar 

  • Tschop M, Meyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML (2001) Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707–709

    Article  PubMed  CAS  Google Scholar 

  • van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 18:7962–7971

    PubMed  Google Scholar 

  • Vuagnat BAM, Pierroz DD, Lalaoui M, Pralong FP, Blum WF, Aubert ML (1998) Evidence for a Leptin-Neuropeptide Y axis for the regulation of Growth Hormone secretion in the rat. Neuroendocrinology 67:291–300

    Article  PubMed  CAS  Google Scholar 

  • Wade GN, Schneider JE, Li H-Y (1996) Control of fertility by metabolic cues. Am J Physiol 270:E1–E19

    PubMed  CAS  Google Scholar 

  • Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L (1998) A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 394:790–793

    Article  CAS  Google Scholar 

  • Williams G, Steel JH, Cardoso H, Ghatei MA, Lee YC, Gill JS, Burrin JM, Polak JM, Bloom SR (1998) Increased hypothalamic neuropeptide Y concentrations in diabetic rats. Diabetes 37:763–772

    Article  Google Scholar 

  • Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterman RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR (2001) Ghrelin causes hyperphagia and obesity in rats. Diabetes 50:2540–2547

    Article  PubMed  CAS  Google Scholar 

  • Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM (1997) Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA 94:1023–1028

    Article  PubMed  CAS  Google Scholar 

  • Yura S, Ogawa Y, Sagawa N, Nasuzaki H, Itoh H, Ebihara K, Aizawa-Abe M, Fujii S, Nakao K (2000) Accelerated puberty and late onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin. J Clin Invest 105:749–755

    Article  PubMed  CAS  Google Scholar 

  • Zachow RJ, Maggofin DA (1997) Direct intraovarian effect of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle stimulating hormone-dependent estradiol-17ß production by rat ovarian granulosa cells. Endocrinology 138:847–850

    Article  PubMed  CAS  Google Scholar 

  • Zamorano PL, Mahesh VB, De Sevilla LM, Chorich LP, Bhat GK, Brann DW (1997a) Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology 65:223–228

    Article  PubMed  CAS  Google Scholar 

  • Zamorano PL, Zachow RJ, Magoffin DA (1997b) Direct intraovarian effects of leptin: impairment of the synergistic action of the insulin-like growth factor I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells. Endocrinology 138:847–850

    Article  Google Scholar 

  • Zhang Y, Proenca R, Maffei M, Barone M, Loepole L, Friedman J (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Biology of Growth and Development, Department of Pediatrics, School of Medicine, 1211, Geneva 14, Switzerland

    M. L. Aubert, B. Sudre, P. D. Raposinho, D. Vauthay & D. D. Pierroz

  2. Division of Endocrinology and Metabolism, Department of Medicine, University School of Medicine, 1011, Lausanne, Switzerland

    F. P. Pralong

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  1. M. L. Aubert
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  2. B. Sudre
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  3. P. D. Raposinho
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  4. D. Vauthay
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  5. D. D. Pierroz
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  6. F. P. Pralong
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Editors and Affiliations

  1. Institut Necker, 156, rue de Vaugirard, 75015, Paris, France

    Claude Kordon

  2. Division of Molecular Neuroendocrinology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Iain Robinson

  3. Service Endocrinologie, Hôpital Henri Mondor — INSERM U.99, 51, Av Mal Lattre de Tassigny, 94010, Creteil

    Jacques Hanoune

  4. INSERM U.394, Rue Camille Saint Säens, 33077, Bordeaux Cedex

    Robert Dantzer

  5. Fondation IPSEN, Pour la Recherche Thérapeutique, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen Ph. D.

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Aubert, M.L., Sudre, B., Raposinho, P.D., Vauthay, D., Pierroz, D.D., Pralong, F.P. (2002). Leptin, Growth and Reproduction. In: Kordon, C., Robinson, I., Hanoune, J., Dantzer, R., Christen, Y. (eds) Brain Somatic Cross-Talk and the Central Control of Metabolism. Research and Perspectives in Endocrine Interactions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18999-9_10

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  • DOI: https://doi.org/10.1007/978-3-642-18999-9_10

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