We have demonstrated previously that pharmacological doses of oestradiol decreased leptin receptor expression in the hypothalamus. We therefore analysed leptin receptor expression during the oestrous cycle in the rat, to establish if acute changes in oestradiol affect leptin receptor expression under physiological conditions. Radioactive in situ hybridization histochemistry was used to measure the gene expression under investigation. Total leptin receptor transcript levels were lowest in pro-oestrus in the choroid plexus, these changes correspond inversely with levels of circulating oestradiol in the rat 4-day oestrous cycle. In contrast full-length leptin receptor levels in both arcuate and ventromedial nuclei did not correspond to the levels of total leptin receptor in the same areas of the hypothalamus or serum levels of oestradiol. Full-length leptin receptor expression in the arcuate nucleus was negatively correlated with neuropeptide Y (NPY) expression (r = 0.447, p < 0.05) in the same nucleus. Arcuate nucleus NPY expression did not correlate significantly with the expression of total leptin receptors in the arcuate nucleus (r = 0.080) or serum leptin levels (r = 0.251). Our results demonstrate that leptin receptor expression is regulated during the oestrous cycle. The unchanged serum leptin levels during the oestrous cycle together with the correlation between the expression of leptin-RL and NPY provide circumstantial evidence that regulation of leptin receptor abundance in the hypothalamus governs the biological actions of leptin.

Keywords:
Leptin, Neuropeptide Y, Leptin receptor, in situ hybridization, Oestrous cycle
1.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM: Positional cloning of the mouse obese gene and its human homologue. Nature 1994;372:425–432.
2.
Coleman DL: Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 1973;9:294–298.
3.
Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P: Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546–549.
4.
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540–543.
5.
Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinwitz D, Lallone RL, Burley SK, Friedman JM: Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:243–246.
6.
Carlsson B, Lindell K, Gabrielsson B, Karlsson C, Bjarnason R, Westphal O, Karlsson V, Sjostrom L, Carlsson LM: Obese (ob) gene defects are rare in human obesity. Obes Res 1997;5:30–35.
7.
Echwald SM, Rasmussen SB, Sorensen TI, Andersen T, Tybjaerg-Hasen R, Clausen JO, Hansen L, Hansen T, Pedersen O: Identification of two novel missense mutations in the human ob gene. Int J Obes Relat Metab Disord 1997;21:321–326.
8.
Montague CT, Farooqui IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Early AR, Barnett AH, Prins JB, O’Rahilly S: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903–908.
9.
Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, Kern PA, Friedman JM: Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight reduced subjects. Nat Med 1995;1:1155–1161.
10.
Campfield LA, Smith FJ, Burn P: The ob protein (leptin) pathway – A link between adipose tissue mass and central neural networks. Horm Metab Res 1996;28:619–632.
11.
Flier JS: Leptin expression and action: New experimental paradigms. Proc Natl Acad Sci USA 1997;94:4242–4245.
12.
Malik KF, Young WS 3rd: Localization of binding sites in the central nervous system for leptin (OB protein) in normal, obese (ob/ob), and diabetic (db/db) C57BL/6J mice. Endocrinology 1996;137:1497–1500.
13.
Lee G-H, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM: Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379:632–635.
14.
Tartaglia LA: The leptin receptor. J Biol Chem 1997;272:6093–6096.
15.
Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP: Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491–495.
16.
Gotoda T, Manning BS, Goldstone AP, Imrie H, Evans AL, Strosberg AD, McKeigue PM, Scott J, Aitman TJ: Leptin receptor gene variation and obesity: Lack of association in a white British male population. Hum Mol Genet 1997;6:869–876.
17.
Chung WK, Power-Kehoe L, Chua M, Chu F, Aronne L, Huma Z, Sothern M, Udall JN, Kahle B, Leibel RL: Exonic and intronic sequence variation in the human leptin receptor gene (LEPR). Diabetes 1997;46:1509–1511.
18.
Matsuoka N, Ogawa Y, Hosoda K, Matsuda J, Masuzaki H, Miyawaki T, Azuma N, Natsui K, Nishimura H, Yoshimasa Y, Nishi S, Thompson DB, Nakao K: Human leptin receptor gene in obese Japanese subjects: Evidence against either obesity-causing mutations or association of sequence variants with obesity. Diabetologia 1997;40:1204–1210.
19.
Rolland V, Clement K, Dugall I, Guy-Grand B, Basdevant A, Froguel P, Lavau M: Leptin receptor gene in a large cohort of massively obese subjects: No indication of the fa/fa rat mutation. Detection of an intronic variant with no association with obesity. Obes Res 1998;6:122–127.
20.
Clement K, Valsse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.
21.
Chung WK, Belfi K, Chua M, Wiley J, Mackintosh R, Nicolson M, Boozer CN, Leibel RL: Heterozygosity for Lep (ob) or Lep (rdb) affects body composition and leptin homeostasis in adult mice. Am J Physiol 1998;274:R985–R990.
22.
Bray GA, Saiduddin S, York DA, Swerdloff RS: Effect of estradiol on uterine weight, thyroid function, food intake, and pituitary weight of genetically obese (fatty-Zucker) and lean rats. Proc Soc Exp Biol Med 1976;153:88–91.
23.
Wade GN: Sex hormones, regulatory behaviours and body weight. Adv Study Behav 1976;6:201–279.
24.
Chehab FF, Mounzih K, Lu R, Lim ME: Early onset of reproductive function in normal female mice treated with leptin. Science 1997;275:88–90.
25.
Bennett PA, Lindell K, Karlsson C, Robinson ICAF, Carlsson LMS, Carlsson B: Differential expression and regulation of leptin receptor isoforms in the rat brain: Effects of fasting and oestrogen. Neuroendocrinology 1998;67:29–36.
26.
Håkansson M-L, Brown H, Ghilardi N, Skoda RC, Mëister B: Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J Neurosci 1998;18:559–572.
27.
Stephens TW, Bashinski M, Bristow PK, Blue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, Mackellar W, Rosteck PR, Schoner B, Smith D, Tinsley FC, Zhang XY, Helman M: The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 1995;377:530–534.
28.
Bennett PA, Wilson C, Lindell K, Carlsson LMS, Carlsson B, Robinson ICAF: Expression of leptin receptor isoforms is differentially regulated during the estrous cycle (abstract P3-246). New Orleans, 80th Annual Meeting of the Endocrine Society, 1998.
29.
Bennett PA, Levy A, Sophokleous S, Robinson ICAF, Lightman SL: Hypothalamic growth hormone receptor gene expression in the rat. J Endocrinol 1995;147:225–234.
30.
Butcher RL, Collins WE, Fugo NW: Plasma concentration of LH, FSH, prolactin, progesterone, and estradiol-17β throughout the 4-day estrus cycle of the rat. Endocrinology 1974;94:1704–1708.
31.
Kalra SP, Kalra PS: Temporal interrelationships among circulating levels of estradiol, progesterone and LH during the rat estrus cycle: Effects of exogenous progesterone. Endocrinology 1974;95:1711–1718.
32.
Gale SK, Van Itallie TB: Genetic obesity: Estrogenic influences on the body weight and food intake of lean and obese adult Zucker (fa/fa) rats. Physiol Behav 1979;23:111–120.
33.
Phillips MS, Liu Q, Hammond HA, Dugan V, Hey PJ, Caskey CT, Hess JF: Leptin receptor missense mutation in the fatty Zucker rat. Nat Genet 1996;13:18–19.
34.
Iida M, Murakami T, Ishida K, Mizuno A, Kuwajima M, Shima K: Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun 1996;222:19–26.
35.
Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel RL: Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab 1996;81:3424–3427.
36.
Saad MF, Damani S, Gingerich RL, Alad-Gabriel MG, Khan A, Boyadjian R, Jinagouda SD, el-Tawll K, Rude RK, Kamdar V: Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab 1997;82:579–584.
37.
Haffner SM, Miettinen H, Karhapaa P, Mykkanen L, Laakso M: Leptin concentrations, sex hormones, and cortisol in non diabetic men. J Clin Endocrinol Metab 1997;82:1807–1809.
38.
Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM: Leptin enters the brain by a saturable system independent of insulin. Peptides 1996;17:305–311.
39.
Pardridge WM: Receptor-mediated peptide transport through the blood-brain barrier. Endocr Rev 1986;7:314–330.
40.
Bauer-Dantoin AC, Urban JH, Levine JE: Neuropeptide Y gene expression in the arcuate nucleus is increased during preovulatory luteinizing hormone surges. Endocrinology 1992;131:2953–2958.
41.
Wilding JPH, Gilbey SG, Bailey CJ, Batt RAL, Williams G, Ghatei MA, Bloom SR: increased neuropeptide-Y messenger robonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology 1993;132:1939–1944.
42.
Sahu A, Phelps CP, White JD, Crowley WR, Kalra SP, Kalra PS: Steroidal regulation of hypothalamic neuropeptide Y release and gene expression. Endocrinology 1992;130:3331–3336.
43.
Sar M, Sahu A, Crowley WR, Kalra SP: Localization of neuropeptide-Y immunoreactivity in estradiol-concentrating cells in the hypothalamus. Endocrinology 1990;127:2752–2756.
44.
Smith FJ, Campfield LA, Moschera JA, Bailon PS, Burn P: Feeding inhibition by neuropeptide Y. Nature 1996;382:307.
45.
Erickson JC, Clegg KE, Palmiter RD: Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 1996;381:415–418.
46.
Vaisse C, Halaas JL, Horvath CM, Darnell JE Jr, Stoffel M, Friedman JM: Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice not db/db mice. Nat Genet 1996;14:95–97.
47.
Carpenter LR, Farruggella TJ, Symes A, Karow ML, Yancopoulos GD, Stahl N: Enhanced leptin response by preventing SH2-containing phosphatase 2 interaction with ob receptor. Proc Natl Acad Sci USA 1998;95:6061–6066.
48.
Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS: Identification of SOCS-3 as a potential mediator of central leptin resistance: Mol Cell 1998;1:619–624.
49.
Gabrielsson BG, Carmignac DF, Flavell DM, Robinson ICAF: Steroid regulation of growth hormone receptor (GHR) and GH binding protein (GHBP) messenger RNAs in the rat. Endocrinology 1995;136:209–217.
50.
Bennett PA, Levy A, Carmignac DF, Robinson ICAF, Lightman SL: Differential regulation of the GH receptor gene: Effects of dexamethasone and estradiol. Endocrinology 1996;137:3891–3896.
1999
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.