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:

Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice

Abstract

OBJECTIVE: To investigate the development of high fat diet-induced obesity and leptin resistance.

DESIGN: Two experiments were carried out in this study. Firstly, we fed the mice with a high- or low-fat diet for up to 19 weeks to examine a progressive development of high fat diet-induced obesity. Secondly, we examined peripheral and central exogenous leptin sensitivity in mice fed high- or low-fat diets for 1, 8 or 19 weeks.

SUBJECTS: A total of 168 C57BL/6J mice (3 weeks old) were used in this study.

MEASUREMENTS: In the first experiment, we measured the body weight, energy intake, adipose tissue mass, tibia bone length, and plasma leptin in mice fed either a high- or low-fat diet for 1, 8, 15 and 19 weeks. In the second experiment, body weight change and cumulative energy intake were measured at 6 h intervals for 72 h after leptin injection in mice fed a high- or low-fat diet for 1, 8 or 19 weeks.

RESULTS: The results from the first experiment suggested that the development of high fat diet-induced obesity in mice could be divided into early, middle and late stages. Compared with the mice fed a low-fat diet, the mice fed a high-fat diet showed a gradually increased body weight (+5.2%), fat storage (epididymal plus perirenal; +6.7%) and plasma leptin (+18%) at 1 week; +11.4%, +68.1%, and +223%, respectively, at 8 weeks; and +30.5%, +141%, and +458%, respectively, at 19 weeks. Energy intake of high fat diet-fed mice was equal to that of low fat diet-fed controls for the first 3 weeks; it fell below control levels over the next 5 week period, but began to increase gradually after 8 weeks of high-fat diet feeding and then increased dramatically from 15 weeks to be 14% higher than that of controls after 19 weeks. The results from our second experiment showed that: (1) after 1 week of feeding, the mice fed a high-fat diet were sensitive to a 2 μg/g (body weight) intraperitoneal (i.p.) injection of leptin, with no differences in body weight change or cumulative energy intake post-injection; (2) after 8 weeks of feeding, the mice fed a high-fat diet were insensitive to 2 μg/g (body weight) i.p. leptin, but were sensitive to a 0.1 μg intracerebroventricular (i.c.v.) injection of leptin; (3) after 19 weeks of feeding, the mice fed a high-fat diet were insensitive to 0.1 μg i.c.v. leptin, but were sensitive to a high dose of 2 μg i.c.v. leptin.

CONCLUSIONS: The present study demonstrated that the development of high fat diet-induced obesity (19 weeks) in C57 B1/6J mice could be divided into three stages: (1) an early stage in response to high-fat diet that mice were sensitive to exogenous leptin; (2) a reduced food intake stage when mice had an increase in leptin production and still retained central leptin sensitivity; and (3) an increased food intake stage, accompanied by a reduction of central leptin sensitivity.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Weiser M, Frishman WH, Michaelson MD, Abdeen MA . The pharmacologic approach to the treatment of obesity J Clin Pharmac 1997 37: 453–473.

    Article  CAS  Google Scholar 

  2. Surwit RS, Kuhn CM, Cochrane C, McCubbin JA, Feinglos MN . Diet-induced type II diabetes in C57BL/6J mice. Diabetes 1988 37: 1163–1167.

    Article  CAS  Google Scholar 

  3. Stunkard AJ . Current views on obesity Am J Med 1996 100: 230–236.

    Article  CAS  Google Scholar 

  4. 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.

    CAS  Google Scholar 

  5. Tartaglia LA, Dembrski 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: 1263–1267.

    Article  CAS  Google Scholar 

  6. 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 mRNA in obese and weight-reduced subjects Nat Med 1995 1: 1155–1161.

    Article  CAS  Google Scholar 

  7. Lee GH, 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.

    Article  CAS  Google Scholar 

  8. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk MJ, 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.

    Article  Google Scholar 

  9. Campfield L, Smith F, Guisez Y, Devos R, Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks Science 1995 269: 546–548.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. Halaas J, Gajiwala K, Maffei M, Cohen S, Chait B, Rabinowitz D, Lallone R, Burley S . Weight reducing effects of the plasma protein encoded by the OB gene Science 1995 269: 543–546.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF . Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity J Clin Invest 1995 95: 2986–2988.

    Article  CAS  Google Scholar 

  14. Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF . The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations Diabetes 1996 45: 992–994.

    Article  Google Scholar 

  15. Niskanen LK, Haffner S, Karhunaen L, Turpeinen AK, Miettinen H, Uusitupa MIJ . Serum leptin in obesity is related to gender and body fat topography but dose not predict successful weigh loss Eur J Endocrinol 1997 137: 61–67.

    Article  CAS  Google Scholar 

  16. Klein S, Coppack SW, Mohamed-Ali V, Landt M . Adipose tissue leptin production and plasma leptin kinetics in humans Diabetes 1996 45: 984–987.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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  CAS  Google Scholar 

  19. Widdowson PS, Upton R, Buckingham R, Arch J, Williams G . Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity Diabetes 1997 46: 1782–1785.

    Article  CAS  Google Scholar 

  20. Lin S, Huang XF . Altered hypothalamic c-Fos expression in diet-induced obese mice Brain Res Bull 1999 49: 215–219.

    Article  CAS  Google Scholar 

  21. Flatt JP . The biochemistry of energy expenditure. In Bray GA (eds) Obesity research II. Newman: London 1978 pp 211–288.

    Google Scholar 

  22. Storlien LH, James DE, Burleigh KM, Chisholm DJ, Kraegen EW . Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats Am J Physiol 1986 251: E576–E583.

    CAS  PubMed  Google Scholar 

  23. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS . Leptin levels reflect lipid content in mice: evidence for diet-induced resistance to leptin action Nature Med 1995 1: 1311–1314.

    Article  CAS  Google Scholar 

  24. Lin S, Huang XF . Fasting increase leptin receptor mRNA expression in lean but not obese (ob/ob) mouse brain. Neuroreport 1997 8: 3625–3629.

    CAS  PubMed  Google Scholar 

  25. Huang XF, Lin S, Zhang R . Upregulation of leptin receptor mRNA expression in obese mouse brain Neuroreport 1996 8: 1035–1038.

    Article  Google Scholar 

  26. Cheung CC, Clifton DK, Steiner RA . Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus Endocrinology 1997 138: 4489–4492.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank Dr Ken Russell (Department of Applied Statistics, University of Wollongong) for suggestions regarding the statistical analysis. This study was supported by grants from the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to XF Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, S., Thomas, T., Storlien, L. et al. Development of high fat diet-induced obesity and leptin resistance in C57Bl/6J mice. Int J Obes 24, 639–646 (2000). https://doi.org/10.1038/sj.ijo.0801209

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0801209

Keywords

Search

Quick links