Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Feb 1;99(3):391–395. doi: 10.1172/JCI119172

Leptin accelerates the onset of puberty in normal female mice.

R S Ahima 1, J Dushay 1, S N Flier 1, D Prabakaran 1, J S Flier 1
PMCID: PMC507811  PMID: 9022071

Abstract

The fat-derived hormone, leptin, is proposed to serve as an adipostatic signal to the brain to reduce food intake and body weight. In addition to its effects on body weight, chronic leptin treatment restores puberty and fertility to ob/ob mice with total leptin deficiency, and acute treatment substantially corrects hypogonadism in mice starved for 2 d without affecting body weight. Leptin may therefore be a critical signal, linking adiposity and reproduction. Since body weight and adiposity appear to play a critical role in the timing of puberty in humans and rodents, and leptin levels rise with increasing adiposity, we studied the effects of once daily injections of recombinant leptin on the onset of puberty in female mice weaned on day 21 and fed ad libitum. There was a linear increase in body weight during the study period, which was not altered by the dose of leptin used. Mice injected with leptin had an earlier onset of three classic pubertal parameters (i.e., vaginal opening, estrus, and cycling) compared with saline-injected controls. Leptin is the first peripheral molecule demonstrated to accelerate the maturation of the reproductive axis in normal rodents. We propose that leptin is the signal that informs the brain that energy stores are sufficient to support the high energy demands of reproduction, and may be a major determinant of the timing of puberty.

Full Text

The Full Text of this article is available as a PDF (147.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahima R. S., Prabakaran D., Mantzoros C., Qu D., Lowell B., Maratos-Flier E., Flier J. S. Role of leptin in the neuroendocrine response to fasting. Nature. 1996 Jul 18;382(6588):250–252. doi: 10.1038/382250a0. [DOI] [PubMed] [Google Scholar]
  2. Banks W. A., Kastin A. J., Huang W., Jaspan J. B., Maness L. M. Leptin enters the brain by a saturable system independent of insulin. Peptides. 1996;17(2):305–311. doi: 10.1016/0196-9781(96)00025-3. [DOI] [PubMed] [Google Scholar]
  3. Barash I. A., Cheung C. C., Weigle D. S., Ren H., Kabigting E. B., Kuijper J. L., Clifton D. K., Steiner R. A. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996 Jul;137(7):3144–3147. doi: 10.1210/endo.137.7.8770941. [DOI] [PubMed] [Google Scholar]
  4. Boyar R. M., Katz J., Finkelstein J. W., Kapen S., Weiner H., Weitzman E. D., Hellman L. Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N Engl J Med. 1974 Oct 24;291(17):861–865. doi: 10.1056/NEJM197410242911701. [DOI] [PubMed] [Google Scholar]
  5. Bronson F. H. Effect of food manipulation on the GnRH-LH-estradiol axis of young female rats. Am J Physiol. 1988 Apr;254(4 Pt 2):R616–R621. doi: 10.1152/ajpregu.1988.254.4.R616. [DOI] [PubMed] [Google Scholar]
  6. Bronson F. H. Mammalian reproduction: an ecological perspective. Biol Reprod. 1985 Feb;32(1):1–26. doi: 10.1095/biolreprod32.1.1. [DOI] [PubMed] [Google Scholar]
  7. Campfield L. A., Smith F. J., Guisez Y., Devos R., Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995 Jul 28;269(5223):546–549. doi: 10.1126/science.7624778. [DOI] [PubMed] [Google Scholar]
  8. Chehab F. F., Lim M. E., Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996 Mar;12(3):318–320. doi: 10.1038/ng0396-318. [DOI] [PubMed] [Google Scholar]
  9. Cioffi J. A., Shafer A. W., Zupancic T. J., Smith-Gbur J., Mikhail A., Platika D., Snodgrass H. R. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996 May;2(5):585–589. doi: 10.1038/nm0596-585. [DOI] [PubMed] [Google Scholar]
  10. Considine R. V., Sinha M. K., Heiman M. L., Kriauciunas A., Stephens T. W., Nyce M. R., Ohannesian J. P., Marco C. C., McKee L. J., Bauer T. L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996 Feb 1;334(5):292–295. doi: 10.1056/NEJM199602013340503. [DOI] [PubMed] [Google Scholar]
  11. De Souza M. J., Metzger D. A. Reproductive dysfunction in amenorrheic athletes and anorexic patients: a review. Med Sci Sports Exerc. 1991 Sep;23(9):995–1007. [PubMed] [Google Scholar]
  12. Frederich R. C., Hamann A., Anderson S., Löllmann B., Lowell B. B., Flier J. S. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995 Dec;1(12):1311–1314. doi: 10.1038/nm1295-1311. [DOI] [PubMed] [Google Scholar]
  13. Frederich R. C., Löllmann B., Hamann A., Napolitano-Rosen A., Kahn B. B., Lowell B. B., Flier J. S. Expression of ob mRNA and its encoded protein in rodents. Impact of nutrition and obesity. J Clin Invest. 1995 Sep;96(3):1658–1663. doi: 10.1172/JCI118206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Frisch R. E., Hegsted D. M., Yoshinaga K. Body weight and food intake at early estrus of rats on a high-fat diet. Proc Natl Acad Sci U S A. 1975 Oct;72(10):4172–4176. doi: 10.1073/pnas.72.10.4172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Frisch R. E., McArthur J. W. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science. 1974 Sep 13;185(4155):949–951. doi: 10.1126/science.185.4155.949. [DOI] [PubMed] [Google Scholar]
  16. Frisch R. E. Pubertal adipose tissue: is it necessary for normal sexual maturation? Evidence from the rat and human female. Fed Proc. 1980 May 15;39(7):2395–2400. [PubMed] [Google Scholar]
  17. Frisch R. E. Weight at menarche: similarity for well-nourished and undernourished girls at differing ages, and evidence for historical constancy. Pediatrics. 1972 Sep;50(3):445–450. [PubMed] [Google Scholar]
  18. Griffin M. L., South S. A., Yankov V. I., Booth R. A., Jr, Asplin C. M., Veldhuis J. D., Evans W. S. Insulin-dependent diabetes mellitus and menstrual dysfunction. Ann Med. 1994 Oct;26(5):331–340. doi: 10.3109/07853899409148347. [DOI] [PubMed] [Google Scholar]
  19. Halaas J. L., Gajiwala K. S., Maffei M., Cohen S. L., Chait B. T., Rabinowitz D., Lallone R. L., Burley S. K., Friedman J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28;269(5223):543–546. doi: 10.1126/science.7624777. [DOI] [PubMed] [Google Scholar]
  20. Innami S., Yang M. G., Mickelsen O., Hafs H. D. The influence of high-fat diets on estrous cycles, sperm production and fertility of rats. Proc Soc Exp Biol Med. 1973 May;143(1):63–68. doi: 10.3181/00379727-143-37253. [DOI] [PubMed] [Google Scholar]
  21. KENNEDY G. C., MITRA J. Body weight and food intake as initiating factors for puberty in the rat. J Physiol. 1963 Apr;166:408–418. doi: 10.1113/jphysiol.1963.sp007112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Maffei M., Halaas J., Ravussin E., Pratley R. E., Lee G. H., Zhang Y., Fei H., Kim S., Lallone R., Ranganathan S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995 Nov;1(11):1155–1161. doi: 10.1038/nm1195-1155. [DOI] [PubMed] [Google Scholar]
  23. McDonald J. K., Lumpkin M. D., DePaolo L. V. Neuropeptide-Y suppresses pulsatile secretion of luteinizing hormone in ovariectomized rats: possible site of action. Endocrinology. 1989 Jul;125(1):186–191. doi: 10.1210/endo-125-1-186. [DOI] [PubMed] [Google Scholar]
  24. Mellon P. L., Windle J. J., Goldsmith P. C., Padula C. A., Roberts J. L., Weiner R. I. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron. 1990 Jul;5(1):1–10. doi: 10.1016/0896-6273(90)90028-e. [DOI] [PubMed] [Google Scholar]
  25. Mitsushima D., Hei D. L., Terasawa E. gamma-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):395–399. doi: 10.1073/pnas.91.1.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nelson J. F., Karelus K., Felicio L. S., Johnson T. E. Genetic influences on the timing of puberty in mice. Biol Reprod. 1990 Apr;42(4):649–655. doi: 10.1095/biolreprod42.4.649. [DOI] [PubMed] [Google Scholar]
  27. Pelleymounter M. A., Cullen M. J., Baker M. B., Hecht R., Winters D., Boone T., Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995 Jul 28;269(5223):540–543. doi: 10.1126/science.7624776. [DOI] [PubMed] [Google Scholar]
  28. Safranski T. J., Lamberson W. R., Keisler D. H. Correlations among three measures of puberty in mice and relationships with estradiol concentration and ovulation. Biol Reprod. 1993 Mar;48(3):669–673. doi: 10.1095/biolreprod48.3.669. [DOI] [PubMed] [Google Scholar]
  29. Schwartz M. W., Seeley R. J., Campfield L. A., Burn P., Baskin D. G. Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 1996 Sep 1;98(5):1101–1106. doi: 10.1172/JCI118891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sinha M. K., Ohannesian J. P., Heiman M. L., Kriauciunas A., Stephens T. W., Magosin S., Marco C., Caro J. F. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 1996 Mar 1;97(5):1344–1347. doi: 10.1172/JCI118551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Smith E. R., Davidson J. M. Role of estrogen in the cerebral control of puberty in female rats. Endocrinology. 1968 Jan;82(1):100–108. doi: 10.1210/endo-82-1-100. [DOI] [PubMed] [Google Scholar]
  32. Stephens T. W., Basinski M., Bristow P. K., Bue-Valleskey J. M., Burgett S. G., Craft L., Hale J., Hoffmann J., Hsiung H. M., Kriauciunas A. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 1995 Oct 12;377(6549):530–532. doi: 10.1038/377530a0. [DOI] [PubMed] [Google Scholar]
  33. Tartaglia L. A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., Richards G. J., Campfield L. A., Clark F. T., Deeds J. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995 Dec 29;83(7):1263–1271. doi: 10.1016/0092-8674(95)90151-5. [DOI] [PubMed] [Google Scholar]
  34. Terasawa E. Control of luteinizing hormone-releasing hormone pulse generation in nonhuman primates. Cell Mol Neurobiol. 1995 Feb;15(1):141–164. doi: 10.1007/BF02069563. [DOI] [PubMed] [Google Scholar]
  35. Urbanski H. F., Ojeda S. R. A role for N-methyl-D-aspartate (NMDA) receptors in the control of LH secretion and initiation of female puberty. Endocrinology. 1990 Mar;126(3):1774–1776. doi: 10.1210/endo-126-3-1774. [DOI] [PubMed] [Google Scholar]
  36. Van der Spuy Z. M. Nutrition and reproduction. Clin Obstet Gynaecol. 1985 Sep;12(3):579–604. [PubMed] [Google Scholar]
  37. Wade G. N., Schneider J. E., Li H. Y. Control of fertility by metabolic cues. Am J Physiol. 1996 Jan;270(1 Pt 1):E1–19. doi: 10.1152/ajpendo.1996.270.1.E1. [DOI] [PubMed] [Google Scholar]
  38. Wetsel W. C. Immortalized hypothalamic luteinizing hormone-releasing hormone (LHRH) neurons: a new tool for dissecting the molecular and cellular basis of LHRH physiology. Cell Mol Neurobiol. 1995 Feb;15(1):43–78. doi: 10.1007/BF02069558. [DOI] [PubMed] [Google Scholar]
  39. Wu F. C., Butler G. E., Kelnar C. J., Huhtaniemi I., Veldhuis J. D. Ontogeny of pulsatile gonadotropin releasing hormone secretion from midchildhood, through puberty, to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay. J Clin Endocrinol Metab. 1996 May;81(5):1798–1805. doi: 10.1210/jcem.81.5.8626838. [DOI] [PubMed] [Google Scholar]
  40. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES