Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Differential and genetically separable associations of leptin with obesity-related traits

International Journal of Obesity volume 24, pages 742–750 (2000)Cite this article

Abstract

OBJECTIVE: The extent to which leptin protects against obesity is unknown. By intercrossing New Zealand obese mice with lean C57BL/6J mice, we have separated the genes controlling leptin and other weight-related phenotypes. This has allowed us to determine whether hyperleptinaemia is associated with reduced food intake and increased physical activity in mice spanning a large range in body weight.

METHODS: Plasma leptin, glucose and insulin, body weight, food intake, running wheel activity, and four adipose depots were measured in 587 adult F2 and backcross mice

RESULTS: When mice were categorized by adiposity, a plot of food intake vs leptin illustrated a U-shaped curve. Food intake decreased as leptin levels rose to ∼15 ng/ml, beyond which the relationship reversed. A negative relationship was observed between activity and leptin with a maximal decrease in activity once leptin reached ∼15 ng/ml.

CONCLUSION: Leptin has differential responses to food intake and activity, suggesting that it has limited potential to defend against obesity. A genetic defect in leptin sensitivity is unlikely to be the primary cause of obesity in these mice, since hyperleptinaemia was not coinherited with both hyperphagia and inactivity as body weight increased.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  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.

    Article  CAS  Google Scholar 

  2. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI . Identification and expression cloning of a leptin receptor, OB-R Cell 1995 83: 1263–1271.

    Article  CAS  Google Scholar 

  3. Scott J . New chapter for the fat controller Nature 1996 379: 113–114.

    Article  CAS  Google Scholar 

  4. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM . Physiological response to long-term peripheral and central leptin infusion in lean and obese mice Proc Natl Acad Sci 1997 94: 8878–8883.

    Article  CAS  Google Scholar 

  5. 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 Nature Med 1995 1: 1155–1161.

    Article  CAS  Google Scholar 

  6. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV . Decreased cerbrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance Lancet 1996 348: 159–161.

    Article  CAS  Google Scholar 

  7. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr . Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans Nature Med 1996 2: 589–593.

    Article  CAS  Google Scholar 

  8. Igel M, Becker W, Herberg L, Joost HG . Hyperleptinemia, leptin resistance, and polymorphic leptin receptor in the New Zealand obese mouse Endocrinology 1997 138: 4234–4239.

    Article  CAS  Google Scholar 

  9. Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR Jr . Diet-induced obese mice develop peripheral, but not central, resistance to leptin J Clin Invest 1997 99:: 385–390.

    Article  Google Scholar 

  10. Niimi M, Sato M, Yokote R, Tada S, Takahara J . Effects of central and peripheral injection of leptin on food intake and on brain Fos expression in the Otsuka Long–Evans Tokushima Fatty rat with hyperleptinemia J Neuroendocrinol 1999 11: 605–611.

    Article  CAS  Google Scholar 

  11. Coleman DL, Hummel KP . Effects of parabiosis of normal with genetically diabetic mice Am J Physiol 1969 217: 1298–1304.

    Article  CAS  Google Scholar 

  12. Lowell BB . Slimming with a leaner enzyme Nature 1996 382: 585–586.

    Article  CAS  Google Scholar 

  13. Mantzoros CS, Qu D, Frederich RC, Susulic VS, Lowell BB, Maratos-Flier E, Flier JS . Activation of β3 adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice Diabetes 1996 45: 909–914.

    Article  CAS  Google Scholar 

  14. Crofford OB, Davis CK . Growth characteristics, glucose tolerance and insulin sensitivity of New Zealand Obese mice Metabolism 1965 14: 271–280.

    Article  CAS  Google Scholar 

  15. Horton RM, Karachunski PI, Kellermann SA, Conti-Fine BM . Simple, inexpensive computerised rodent activity meters Biotechniques 1995 19: 594–597.

    CAS  PubMed  Google Scholar 

  16. Finger FW . Estrus and general activity in the rat J Comp Physiol Psychol 1969 68: 461–466.

    Article  CAS  Google Scholar 

  17. Boston BA, Blaydon KM, Vernerin J, Cone RD . Independent and additive effects of central POMC and leptin pathways on murine obesity Science 1997 278: 1641–1644.

    Article  CAS  Google Scholar 

  18. Malik KF, Young WF . Localization of binding sites in the central nervous system for leptin in normal, obese (ob/ob) and diabetic (db/db) C57BL/6J mice Endocrinology 1996 137: 1497–1500.

    Article  CAS  Google Scholar 

  19. 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: 619–625.

    Article  CAS  Google Scholar 

  20. Rizk NM, Liu LS, Eckel J . Hypothalamic expression of neuropeptide-Y in the New Zealand obese mouse Int J Obes Relat Metab Disord 1998 22: 1172–1177.

    Article  CAS  Google Scholar 

  21. 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: 540–546.

    Article  CAS  Google Scholar 

  22. Martin LJ, Jones PJ, Considine RV, Su W, Boyd NF, Caro JF . Serum leptin levels and energy expenditure in normal weight women Can J Physiol Pharmacol 1998 76: 237–241.

    Article  CAS  Google Scholar 

  23. Nicklas BJ, Toth MJ, Poehlman ET . Daily energy expenditure is related to plasma leptin concentrations in older African-American women but not men Diabetes 1997 46:: 1389–1392.

    Article  Google Scholar 

  24. Salbe AD, Nicolson M, Ravussin E . Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children J Clin Invest 1997 99: 592–595.

    Article  CAS  Google Scholar 

  25. Levine JA, Eberhardt NL, Jensen MD . Leptin responses to overfeeding: relationship with body fat and nonexercise activity thermogenesis J Clin Endocrinol Metab 1999 84: 2751–2754.

    CAS  PubMed  Google Scholar 

  26. Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q, Garvey WT . The metabolic significance of leptin in humans: gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure J Clin Endocrinol Metab 1997 82: 1293–1300.

    CAS  PubMed  Google Scholar 

  27. Nyholm B, Fisker S, Lund S, Moller N, Schmitz O . Increased circulating leptin concentrations in insulin-resistant first-degree relatives of patients with non-insulin-dependent diabetes mellitus: relationship to body composition and insulin sensitivity but not to family history of non-insulin-dependent diabetes mellitus Eur J Endocrinol 1997 136: 173–179.

    Article  CAS  Google Scholar 

  28. Niskanen L, Haffner S, Karhunen LJ, Turpeinen AK, Miettinen H, Uusitupa MI . Serum leptin in relation to resting energy expenditure and fuel metabolism in obese subjects Int J Obes Relat Metab Disord 1997 2l: 309–313.

    Article  Google Scholar 

  29. Toth MJ, Sites CK, Poehlman ET . Hormonal and physiological correlates of energy expenditure and substrate oxidation in middle-aged, premenopausal women J Clin Endocrinol Metab 1999 84: 2771–2775.

    CAS  PubMed  Google Scholar 

  30. Farooqi IS, Jebb SA, Langmack G, Lawrence E et al.Effects of recombinant leptin therapy in a child with congenital leptin deficiency N Engl J Med 1999 341: 879–884.

    Article  CAS  Google Scholar 

  31. Roberts SB, Savage J, Coward WA, Chew B, Lucas A . Energy expenditure and intake in infants born to lean and overweight mothers N Engl J Med 1988 318: 461–466.

    Article  CAS  Google Scholar 

  32. Ravussin E, Lillioja S, Anderson TE, Christin L, Bogardus C . Determinants of 24-h energy expenditure in man. Methods and results using a respiratory chamber J Clin Invest 1986 78: 1568–1578.

    Article  CAS  Google Scholar 

  33. Toubo S, Christensen NJ, Astrup A . Reproducibility of 24-h energy expenditure, substrate utilization and spontaneous physical activity in obesity measured in a respiration chamber Int J Obes Relat Metab Disord 1995 19: 544–549.

    Google Scholar 

  34. Zurlo F, Ferraro RT, Fontvielle AM, Rising R, Bogardus C, Ravussin E . Spontaneous physical activity and obesity: cross-sectional and longitudinal studies in Pima Indians Am J Physiol 1992 263: E296–E300.

    CAS  PubMed  Google Scholar 

  35. Pereira HS, Sorkolowski MB . Mutations in the larval foraging gene affect locomotory behavior after feeding in Drosophila melanogaster Proc Natl Acad Sci USA 1993 90: 5044–5046.

    Article  CAS  Google Scholar 

  36. Belknap JK, Riggan J, Cross S, Young ER, Gallaher EJ, Crabbe JC . Genetic determinants of morphine activity and thermal responses in 15 inbred mouse strains Pharmacol Biochem Behav 1998 59: 353–360.

    Article  CAS  Google Scholar 

  37. Bielschowsky M, Bielschowsky F . The New Zealand strain of obese mice. Their response to stilboestrol and to insulin Aust J Exp Biol 1956 34: 181–198.

    Article  CAS  Google Scholar 

  38. Pettitt DJ, Baird R, Aleck KA, Bennett PH, Knowler WC . Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy N Engl J Med 1983 308: 242–245.

    Article  CAS  Google Scholar 

  39. Bihoreau MT, Ktorza A, Kinebanyan MF, Picon L . Impaired glucose homeostasis in adult rats from hyperglycemic mothers Diabetes 1986 35: 979–984.

    Article  CAS  Google Scholar 

  40. Aerts L, Holemans K, Van Assche FA . Maternal diabetes during pregnancy: consequences for the offspring Diabetes Metab Rev 1990 6: 147–167.

    Article  CAS  Google Scholar 

  41. Prentice AM, Jebb SA . Obesity in Britain: gluttony or sloth? BMJ 1995 311: 437–439.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Marisa Fielding, Sue Fabris and Jenny Huang from the Department of Medicine and Brigid Shore and Katie Sells from the WEHI for technical assistance. This study was supported by a National Health and Medical Research Council of Australia Project Grant and a National Heart Foundation of Australia grant.

Author information

Authors and Affiliations

  1. Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Melbourne, Australia

    AW Thorburn & J Proietto

  2. Walter and Eliza Hall Institute, Parkville, 3050, Victoria, Australia

    A Holdsworth & G Morahan

Authors
  1. AW Thorburn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Holdsworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Proietto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G Morahan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to AW Thorburn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thorburn, A., Holdsworth, A., Proietto, J. et al. Differential and genetically separable associations of leptin with obesity-related traits. Int J Obes 24, 742–750 (2000). https://doi.org/10.1038/sj.ijo.0801213

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801213

Keywords

Search

Advanced search

Quick links