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.

  • Letter
  • Published:

A nutrient-sensing pathway regulates leptin gene expression in muscle and fat

Nature volume 393, pages 684–688 (1998)Cite this article

Abstract

Leptin, the protein encoded by the obese (ob) gene, is synthesized and released in response to increased energy storage in adipose tissue1,2,3,4. However, it is still not known how incoming energy is sensed and transduced into increased expression of the ob gene. The hexosamine biosynthetic pathway is a cellular ‘sensor’ of energy availability5,6,7,8 and mediates the effects of glucose on the expression of several gene products9,10,11,12. Here we provide evidence for rapid activation of ob gene expression in skeletal muscle by glucosamine. Increased tissue concentrations of the end product of the hexosamine biosynthetic pathway, UDP-N-acetylglucosamine (UDP-GlcNAc), result in rapid and marked increases in leptin messenger RNA and protein levels (although these levels were much lower than those in fat). Plasma leptin levels and leptin mRNA and protein levels in adipose tissue also increase. Most important, stimulation of leptin synthesis is reproduced by either hyperglycaemia or hyperlipidaemia, which also increase tissue levels of UDP-N-acetylglucosamine in conscious rodents7. Finally, incubation of 3T3-L1 pre-adipocytes and L6 myocytes with glucosamine rapidly induces ob gene expression. Our findings are the first evidence of inducible leptin expression in skeletal muscle and unveil an important biochemical link between increased availability of nutrients and leptin expression.

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: Sites of entry of glucose, GlcN and uridine into the hexosamine biosynthetic pathway in skeletal muscle and the role of free fatty acids (FFAs).
Figure 2: We studied levels of leptin mRNAs in different tissues by RT-PCR and northern blot analysis.
Figure 3: Leptin gene expression in fat tissues.
Figure 4: Immunohistochemical analysis of leptin in muscle tissue obtained from Sprague–Dawley rats.

Similar content being viewed by others

References

  1. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  ADS  CAS  Google Scholar 

  2. Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540–543 (1995).

    Article  ADS  CAS  Google Scholar 

  3. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

    Article  ADS  CAS  Google Scholar 

  4. Campfield, L., 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 269, 546–549 (1995).

    Article  ADS  CAS  Google Scholar 

  5. Marshall, S., Bacote, V. & Traxinger, R. R. Discovery of a metabolic pathway mediating desensitization of the glucose transport system: role of hexosamine biosynthesis in the induction of insulin resistance. J. Biol. Chem. 266, 4706–4712 (1991).

    CAS  PubMed  Google Scholar 

  6. Rossetti, L., Hawkins, M., Chen, W., Gindi, J. & Barzilai, N. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J. Clin. Invest. 96, 132–140 (1995).

    Article  CAS  Google Scholar 

  7. Hawkins, M., Barzilai, N., Hu, M., Chen, W. & Rossetti, L. Role of the glucosamine pathway in fat-induced insulin resistance. J. Clin. Invest. 99, 2173–2182 (1997).

    Article  CAS  Google Scholar 

  8. Hawkins, M. et al. The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake. J. Biol. Chem. 272, 4889–4895 (1997).

    Article  CAS  Google Scholar 

  9. Sayeski, P. P. & Kudlow, J. E. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-a gene transcription. J. Biol. Chem. 271, 15237–15243 (1996).

    Article  CAS  Google Scholar 

  10. Daniels, M. C. et al. Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway. Mol. Endocrinol. 7, 1041–1048 (1993).

    CAS  PubMed  Google Scholar 

  11. McClain, D., Paterson, A., Roos, M., Wei, X. & Kudlow, J. Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc. Natl Acad. Sci. USA 89, 8150–8154 (1992).

    Article  ADS  CAS  Google Scholar 

  12. Han, I. & Kudlow, J. E. Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol. Cell. Biol. 17, 2550–2558 (1997).

    Article  CAS  Google Scholar 

  13. Rossetti, L., Smith, D., Shulman, G. I., Papachristou, D. & DeFronzo, R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510–1515 (1987).

    Article  CAS  Google Scholar 

  14. Hu, E., Liang, P. & Spiegelman, B. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J.Biol. Chem. 271, 10697–10703 (1996).

    Article  CAS  Google Scholar 

  15. Gong, D.-W., He, Y., Karas, M. & Reitman, M. Uncoupling protein-3 is a mediator of thermogenesis regulated by thyroid hormone, b3-adrenergic agonists, and leptin. J. Biol. Chem. 272, 24129–24132 (1997).

    Article  CAS  Google Scholar 

  16. Schwartz, M. W., Peskind, E., Raskind, M., Boyko, E. J. & Porte, D. J. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nature Med. 2, 589–593 (1996).

    Article  CAS  Google Scholar 

  17. Flier, J. S. Leptin expression and action: new experimental paradigms. Proc. Natl Acad. Sci. USA 94, 4242–4245 (1997).

    Article  ADS  CAS  Google Scholar 

  18. Ahima, R. S. et al. Role of leptin in the neuroendocrine respone to fasting. Nature 382, 250–252 (1996).

    Article  ADS  CAS  Google Scholar 

  19. Boden, G., Chen, X., Mozzolo, M. & Ryan, I. Effect of fasting on serum leptin in normal human subjects. J. Clin. Endocrinol. Metab. 81, 3419–3423 (1996).

    CAS  PubMed  Google Scholar 

  20. Kolaczynski, J. W. et al. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes 45, 1511–1515 (1996).

    Article  CAS  Google Scholar 

  21. Saladin, R. et al. Transient increase in obese gene expression after good intake or insulin administration. Nature 377, 527–529 (1995).

    Article  ADS  CAS  Google Scholar 

  22. Kolaczynski, J. W. et al. Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 45, 699–701 (1996).

    Article  CAS  Google Scholar 

  23. MacDougald, O. A., Hwang, C. S., Fan, H. & Lane, M. D. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adpocytes. Proc. Natl Acad. Sci. USA 92, 9034–9037 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Segal, K. R., Landt, M. & Klein, S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes 45, 988–991 (1996).

    Article  CAS  Google Scholar 

  25. Baron, A. et al. Glucosamine induces insulin resistance in vivo by affecting GLUT4 translocation in skeletal muscle. J. Clin. Invest. 96, 2792–2801 (1995).

    Article  CAS  Google Scholar 

  26. Hebert, L. et al. Overexpression of glutamine:fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance. J. Clin. Invest. 98, 930–936 (1996).

    Article  CAS  Google Scholar 

  27. Robinson, K. A., Sens, D. A. & Buse, M. G. Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Diabetes 42, 1333–1346 (1993).

    Article  CAS  Google Scholar 

  28. Wang, J., Hawkins, M. & Rossetti, L. Glutamine:fructose-6-P admidotransferase (GFA) gene expression is induced by glucosamine flux in skeletal muscle. Diabetes 46 (suppl.), 325 (1997).

    Google Scholar 

  29. Muoio, D. M., Dohn, G. L., Fiedorek, F. T., Tapscott, E. B. & Coleman, R. A. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 46, 1360–1363 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank M. Hu and W. Chen for technical assistance. This work was supported by grants from the NIH and the American Diabetes Association and by the Albert Einstein Diabetes Research and Training Center. L.R. is the recipient of a Career Scientist Award from the Irma T. Hirschl Trust and N.B. of the Beeson Physician Faculty Scholar in Aging Award.

Author information

Authors and Affiliations

  1. Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Jiali Wang, Rong Liu, Meredith Hawkins, Nir Barzilai & Luciano Rossetti

Authors
  1. Jiali Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Meredith Hawkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nir Barzilai
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Luciano Rossetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luciano Rossetti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, J., Liu, R., Hawkins, M. et al. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684–688 (1998). https://doi.org/10.1038/31474

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/31474

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing