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.

Hypothalamic KATP channels control hepatic glucose production

Nature volume 434, pages 1026–1031 (2005)Cite this article

Abstract

Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus1,2. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis3. The medial hypothalamus is a major integrator of nutritional and hormonal signals1,2,4, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output5,6. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance7,8,9,10 and glucose metabolism5. Here we show that activation of ATP-sensitive potassium (KATP) channels11 in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a KATP blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the KATP channel12 are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic KATP channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Activation of hypothalamic KATP channels lowers plasma glucose by inhibiting glucose production.
Figure 2: Role of SUR1 and efferent vagus in hepatic insulin action.
Figure 3: Hepatic vagus and activation of hypothalamic KATP channels are required for the effect of physiological hyperinsulinaemia on glucose production.

Similar content being viewed by others

References

  1. Friedman, J. M. A war on obesity, not the obese. Science 299, 856–858 (2003)

    Article  ADS  CAS  Google Scholar 

  2. Flier, J. S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004)

    Article  CAS  Google Scholar 

  3. Magnusson, I., Rothman, D. L., Katz, L. D., Shulman, R. G. & Shulman, G. I. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J. Clin. Invest. 90, 1323–1327 (1992)

    Article  CAS  Google Scholar 

  4. Schwartz, M. W., Woods, S. C., Porte, D. Jr, Seeley, R. J. & Baskin, D. G. Central nervous system control of food intake. Nature 404, 661–671 (2000)

    Article  CAS  Google Scholar 

  5. Obici, S., Zhang, B. B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nature Med. 8, 1376–1382 (2002)

    Article  CAS  Google Scholar 

  6. Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Med. 9, 756–761 (2003)

    Article  CAS  Google Scholar 

  7. Obici, S., Feng, Z., Karkanias, G., Baskin, D. G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nature Neurosci. 5, 566–572 (2002)

    Article  CAS  Google Scholar 

  8. Bruning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000)

    Article  ADS  CAS  Google Scholar 

  9. Woods, S. C., Lotter, E. C., McKay, L. D. & Porte, D. Jr Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979)

    Article  ADS  CAS  Google Scholar 

  10. Niswender, K. D. et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 52, 227–231 (2003)

    Article  CAS  Google Scholar 

  11. Aguilar-Bryan, L. & Bryan, J. Molecular biology of adenosine triphosphate-sensitive potassium channels. Endocr. Rev. 20, 101–135 (1999)

    CAS  PubMed  Google Scholar 

  12. Seghers, V., Nakazaki, M., DeMayo, F., Aguilar-Bryan, L. & Bryan, J. Sur1 knockout mice. A model for KATP channel-independent regulation of insulin secretion. J. Biol. Chem. 275, 9270–9277 (2000)

    Article  CAS  Google Scholar 

  13. Karschin, C., Ecke, C., Ashcroft, F. M. & Karschin, A. Overlapping distribution of KATP channel-forming Kir6.2 subunit and the sulfonylurea receptor SUR1 in rodent brain. FEBS Lett. 401, 59–64 (1997)

    Article  CAS  Google Scholar 

  14. Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D. & Ashford, M. L. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997)

    Article  ADS  CAS  Google Scholar 

  15. Spanswick, D., Smith, M. A., Mirshamsi, S., Routh, V. H. & Ashford, M. L. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nature Neurosci. 3, 757–758 (2000)

    Article  CAS  Google Scholar 

  16. Grill, H. J. et al. Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143, 239–246 (2002)

    Article  CAS  Google Scholar 

  17. Aguilar-Bryan, L. et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268, 423–426 (1995)

    Article  ADS  CAS  Google Scholar 

  18. Seino, S. & Miki, T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog. Biophys. Mol. Biol. 81, 133–176 (2003)

    Article  CAS  Google Scholar 

  19. Seino, S., Iwanaga, T., Nagashima, K. & Miki, T. Diverse roles of KATP channels learned from Kir6.2 genetically engineered mice. Diabetes 49, 311–318 (2000)

    Article  CAS  Google Scholar 

  20. Chutkow, W. A. et al. Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proc. Natl Acad. Sci. USA 98, 11760–11764 (2001)

    Article  ADS  CAS  Google Scholar 

  21. Matsuhisa, M. et al. Important role of the hepatic vagus nerve in glucose uptake and production by the liver. Metabolism 49, 11–16 (2000)

    Article  CAS  Google Scholar 

  22. Loftus, T. M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000)

    Article  ADS  CAS  Google Scholar 

  23. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004)

    Article  ADS  CAS  Google Scholar 

  24. Obici, S. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002)

    Article  CAS  Google Scholar 

  25. Pocai, A., Obici, S., Schwartz, G. J. & Rossetti, L. A brain–liver circuit regulates glucose homeostasis. Cell Metab. 1, 53–61 (2005)

    Article  CAS  Google Scholar 

  26. Morton, G. J. et al. Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats. Endocrinology 144, 2016–2024 (2003)

    Article  CAS  Google Scholar 

  27. Massillon, D. et al. Quantitation of hepatic glucose fluxes and pathways of hepatic glycogen synthesis in conscious mice. Am. J. Physiol. 269, E1037–E1043 (1995)

    CAS  PubMed  Google Scholar 

  28. la Fleur, S. E., Ji, H., Manalo, S. L., Friedman, M. I. & Dallman, M. F. The hepatic vagus mediates fat-induced inhibition of diabetic hyperphagia. Diabetes 52, 2321–2330 (2003)

    Article  CAS  Google Scholar 

  29. Norgren, R. & Smith, G. P. Central distribution of subdiaphragmatic vagal branches in the rat. J. Comp. Neurol. 273, 207–223 (1988)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank B. Liu, S. Gaweda and C. Baveghems for expert technical assistance. This work was supported by the NIH, ADA and the Skirball Foundation.

Author information

Authors and Affiliations

  1. Departments of Medicine, Neuroscience and Molecular Pharmacology, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, 10461, USA

    Alessandro Pocai, Tony K. T. Lam, Roger Gutierrez-Juarez, Silvana Obici, Gary J. Schwartz & Luciano Rossetti

  2. Department of Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA

    Joseph Bryan & Lydia Aguilar-Bryan

Authors
  1. Alessandro Pocai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tony K. T. Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Roger Gutierrez-Juarez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvana Obici
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gary J. Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Joseph Bryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lydia Aguilar-Bryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luciano Rossetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luciano Rossetti.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures S1-S3

Supplementary Figure S1 shows that the activation of hypothalamic KATP channels lowers plasma glucose through inhibition of GP. Supplementary Figure S2 details the expression of SUR mRNA within the hypothalamus and effect of ICV insulin on glucose kinetics. Supplementary Figure S3 demonstrates that the hepatic vagus and activation of hypothalamic KATP channels are required for the effect of physiological hyperinsulinemia on GP. (PDF 1006 kb)

Supplementary Figure Legends

This file contains Supplementary Figure Legends for Supplementary Figures S1-S3. (DOC 27 kb)

Supplementary Tables S1-S8

This file contain the Supplementary Tables with metabolic parameters before and during the clamp and the specific activities of substrates used to calculate the hepatic glucose fluxes. (DOC 124 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pocai, A., Lam, T., Gutierrez-Juarez, R. et al. Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031 (2005). https://doi.org/10.1038/nature03439

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03439

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