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.

Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

Abstract

A subset of neurons in the brain, known as ‘glucose-excited’ neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic β-cells1, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (KATP) channels2,3,4,5. Although β-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons5 via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of KATP channels6,7. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production8. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Glucose sensing is lost in POMC-mut-Kir6.2 neurons.
Figure 2: Glucose-sensing is lost in POMC neurons of mice on a high-fat diet.
Figure 3: Genipin activates glucose-excited POMC neurons.
Figure 4: Acute inhibition or genetic deletion of UCP2 restores or prevents loss of glucose sensing in POMC neurons as a result of obesity induced by a high-fat diet.

References

  1. Ashcroft, F. M., Harrison, D. E. & Ashcroft, S. J. Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312, 446–448 (1984)

    ADS  CAS  Article  Google Scholar 

  2. Ashford, M. L., Boden, P. R. & Treherne, J. M. Glucose-induced excitation of hypothalamic neurones is mediated by ATP-sensitive K+ channels. Pflugers Arch. 415, 479–483 (1990)

    CAS  Article  Google Scholar 

  3. Miki, T. et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nature Neurosci. 4, 507–512 (2001)

    CAS  Article  Google Scholar 

  4. Kang, L., Routh, V. H., Kuzhikandathil, E. V., Gaspers, L. D. & Levin, B. E. Physiological and molecular characteristics of rat hypothalamic ventromedial nucleus glucosensing neurons. Diabetes 53, 549–559 (2004)

    CAS  Article  Google Scholar 

  5. Ibrahim, N. et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express KATP channels. Endocrinology 144, 1331–1340 (2003)

    CAS  Article  Google Scholar 

  6. Koster, J. C., Marshall, B. A., Ensor, N., Corbett, J. A. & Nichols, C. G. Targeted overactivity of β cell KATP channels induces profound neonatal diabetes. Cell 100, 645–654 (2000)

    CAS  Article  Google Scholar 

  7. Koster, J. C., Sha, Q., Shyng, S. & Nichols, C. G. ATP inhibition of KATP channels: control of nucleotide sensitivity by the N-terminal domain of the Kir6.2 subunit. J. Physiol. (Lond.) 515, 19–30 (1999)

    CAS  Article  Google Scholar 

  8. Zhang, C. Y. et al. Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β cell dysfunction, and type 2 diabetes. Cell 105, 745–755 (2001)

    CAS  Article  Google Scholar 

  9. Balthasar, N. et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004)

    CAS  Article  Google Scholar 

  10. Silver, I. A. & Erecinska, M. Extracellular glucose concentration in mammalian brain: continuous monitoring of changes during increased neuronal activity and upon limitation in oxygen supply in normo-, hypo-, and hyperglycemic animals. J. Neurosci. 14, 5068–5076 (1994)

    CAS  Article  Google Scholar 

  11. Enriori, P. J. et al. Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metab. 5, 181–194 (2007)

    CAS  Article  Google Scholar 

  12. Poitout, V. & Robertson, R. P. Minireview: Secondary β-cell failure in type 2 diabetes–a convergence of glucotoxicity and lipotoxicity. Endocrinology 143, 339–342 (2002)

    CAS  Article  Google Scholar 

  13. Lowell, B. B. & Shulman, G. I. Mitochondrial dysfunction and type 2 diabetes. Science 307, 384–387 (2005)

    ADS  CAS  Article  Google Scholar 

  14. Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002)

    ADS  CAS  Article  Google Scholar 

  15. Krauss, S., Zhang, C. Y. & Lowell, B. B. A significant portion of mitochondrial proton leak in intact thymocytes depends on expression of UCP2. Proc. Natl Acad. Sci. USA 99, 118–122 (2002)

    ADS  CAS  Article  Google Scholar 

  16. Laybutt, D. R. et al. Genetic regulation of metabolic pathways in β-cells disrupted by hyperglycemia. J. Biol. Chem. 277, 10912–10921 (2002)

    CAS  Article  Google Scholar 

  17. Krauss, S. et al. Superoxide-mediated activation of uncoupling protein 2 causes pancreatic β cell dysfunction. J. Clin. Invest. 112, 1831–1842 (2003)

    CAS  Article  Google Scholar 

  18. Joseph, J. W. et al. Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51, 3211–3219 (2002)

    CAS  Article  Google Scholar 

  19. Zhang, C. Y. et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced β cell dysfunction in isolated pancreatic islets. Cell Metab. 3, 417–427 (2006)

    CAS  Article  Google Scholar 

  20. Joseph, J. W. et al. Free fatty acid-induced β -cell defects are dependent on uncoupling protein 2 expression. J. Biol. Chem. 279, 51049–51056 (2004)

    CAS  Article  Google Scholar 

  21. Horvath, T. L. et al. Brain uncoupling protein 2: uncoupled neuronal mitochondria predict thermal synapses in homeostatic centers. J. Neurosci. 19, 10417–10427 (1999)

    CAS  Article  Google Scholar 

  22. Richard, D., Clavel, S., Huang, Q., Sanchis, D. & Ricquier, D. Uncoupling protein 2 in the brain: distribution and function. Biochem. Soc. Trans. 29, 812–817 (2001)

    CAS  Article  Google Scholar 

  23. Richard, D. et al. Distribution of the uncoupling protein 2 mRNA in the mouse brain. J. Comp. Neurol. 397, 549–560 (1998)

    CAS  Article  Google Scholar 

  24. Mountjoy, P. D., Bailey, S. J. & Rutter, G. A. Inhibition by glucose or leptin of hypothalamic neurons expressing neuropeptide Y requires changes in AMP-activated protein kinase activity. Diabetologia 50, 168–177 (2007)

    CAS  Article  Google Scholar 

  25. Burdakov, D., Gerasimenko, O. & Verkhratsky, A. Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J. Neurosci. 25, 2429–2433 (2005)

    CAS  Article  Google Scholar 

  26. Routh, V. H. Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) and hypoglycemia-associated autonomic failure (HAAF). Diabetes Metab. Res. Rev. 19, 348–356 (2003)

    CAS  Article  Google Scholar 

  27. Dallaporta, M., Perrin, J. & Orsini, J. C. Involvement of adenosine triphosphate-sensitive K+ channels in glucose-sensing in the rat solitary tract nucleus. Neurosci. Lett. 278, 77–80 (2000)

    CAS  Article  Google Scholar 

  28. Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001)

    ADS  CAS  Article  Google Scholar 

  29. Dhillon, H. et al. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49, 191–203 (2006)

    CAS  Article  Google Scholar 

  30. Perkins, K. L. Cell-attached voltage-clamp and current-clamp recording and stimulation techniques in brain slices. J. Neurosci. Methods 154, 1–18 (2006)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank J. Koster and C. Nichols for donation of the Kir6.2[ΔN2–30,K185Q]–GFP construct; Z. Yang, L. Christiansen, M. Kramer and S. Skowronek for animal care and technical assistance; and B. Bean for discussions, guidance with electrophysiological experiments and for critical reading of this manuscript. This work was supported by NIH grants (B.B.L., J.K.E., M.A.C., P.J.E.); a Smith Family Pinnacle Award from the American Diabetes Association (J.K.E.); a National Natural Science Foundation of China Outstanding Young Scientist Award; the National Basic Research Program of China (973 Program); the ‘111’ Project; and the Natural Science Foundation of Jiangsu Province (C.-Y.Z.).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Michael A. Cowley or Bradford B. Lowell.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Data with a full description of studies used to characterize the ATP sensitivity of both wild-type and mutKir6.2 POMC neurons in addition to whole-cell recordings showing effects of glucose, genipin and leptin. Also, Supplementary Figure S1 displays RT-PCR results showing tissue specific expression of mutKir6.2 and characterization of KATP channels in mutKir6.2 POMC neurons; and Supplementary Figure S2 displays whole cell electrophysiological recordings of wild-type and mutKir6.2 POMC neurons showing effects of glucose, genipin and leptin. (PDF 692 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Parton, L., Ye, C., Coppari, R. et al. Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity. Nature 449, 228–232 (2007). https://doi.org/10.1038/nature06098

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06098

Further reading

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

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