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Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels

Nature volume 390, pages 521–525 (1997)Cite this article

Abstract

Leptin, the protein encoded by the obese (ob ) gene, is secreted from adipose tissue and is thought to act in the central nervous system to regulate food intake and body weight1,2. It has been proposed that leptin acts in the hypothalamus3,4,5, the main control centre for satiety and energy expenditure6. Mutations in leptin or the receptor isoform (Ob-RL) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes7,8,9,10. Here we show that leptin hyperpolarizes glucose-receptive hypothalamic neurons of lean Sprague–Dawley and Zucker rats, but is ineffective on neurons of obese Zucker (fa/fa ) rats. This hyperpolarization is due to the activation of a potassium current, and is not easily recovered on removal of leptin, but is reversed by applying the sulphonylurea, tolbutamide. Single-channel recordings demonstrate that leptin activates an ATP-sensitive potassium (KATP) channel. Our data indicate that the KATP channel may function as the molecular end-point of the pathway following leptin activation of the Ob-RL receptor in hypothalamic neurons.

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Figure 1: Leptin hyperpolarizes hypothalamic neurons by activation of a K+conductance.
Figure 2: Leptin increases K+conductance in GR neurons of Sprague-Dawley, Zucker lean but not obese Zucker rats.
Figure 3: Activation of single, tolbutamide-sensitive K+channels by leptin.
Figure 4: Leptin activates KATP channels in a membrane-delimited manner.

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References

  1. Caro, J. F., Sinha, M. K., Kolaczynski, J. W., Zhang, P. L. & Considine, R. V. Leptin: The tale of an obesity gene. Diabetes 45, 1455–1462 (1996).

    Article  CAS  Google Scholar 

  2. Matson, C. A., Wiater, M. F. & Weigle, D. S. Leptin and the regulation of body adiposity. Diabetes Rev. 4, 488–508 (1996).

    Google Scholar 

  3. Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–532 (1995).

    Article  ADS  CAS  Google Scholar 

  4. Satoh, N. et al. The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci. Lett. 224, 149–152 (1997).

    Article  CAS  Google Scholar 

  5. Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nature Genet. 14, 95–97 (1996).

    Article  CAS  Google Scholar 

  6. Levin, B. E. & Routh, V. H. Role of the brain in energy balance and obesity. Am. J. Physiol. 40, R491–R500 (1996).

    Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  8. Lee, G.-H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    Article  ADS  CAS  Google Scholar 

  9. Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).

    Article  CAS  Google Scholar 

  10. Chua, S. C. J et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271, 994–996 (1996).

    Article  ADS  CAS  Google Scholar 

  11. Oomura, Y., Ono, T., Ooyama, H. & Wayner, M. J. Glucose and osmosensitive neurones in the rat hypothalamus. Nature 222, 282–284 (1969).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Ashford, M. L. J., Boden, P. R. & Treherne, J. M. Tolbutamide excites rat glucoreceptive ventromedial hypothalamic neurones by indirect inhibition of ATP-K+ channels. Br. J. Pharmacol. 101, 531–540 (1990).

    Article  CAS  Google Scholar 

  14. Streamson, C. et al. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr ). Diabetes 45, 1141–1143 (1996).

    Article  Google Scholar 

  15. Phillips, M. S. et al. Leptin receptor missense mutation in the fatty Zucker rat. Nature Genet. 13, 18–19 (1996).

    Article  CAS  Google Scholar 

  16. Rosenblum, C. I. et al. Functional STAT 1 and 3 signalling by the leptin receptor (OB-R); reduced expression of the fatty leptin receptor in transfected cells. Endocrinology 137, 5178–5181 (1996).

    Article  CAS  Google Scholar 

  17. Yamashita, T., Murakami, T., Iida, M., Kuwajima, M. & Shima, K. Leptin receptor of Zucker fatty rat performs reduced signal transduction. Diabetes 46, 1077–1080 (1997).

    Article  CAS  Google Scholar 

  18. Treherne, J. M. & Ashford, M. L. J. Calcium-activated potassium channels in rat dissociated ventromedial hypothalamic neurones. J. Neuroendocrinol. 3, 323–329 (1991).

    Article  CAS  Google Scholar 

  19. Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    Article  CAS  Google Scholar 

  20. Rock, F. L., Peterson, D., Weig, B. C., Kastelein, R. A. & Bazan, J. F. Binding of leptin to the soluble ectodomain of recombinant leptin receptor. Horm. Metab. Res. 28, 748–750 (1996).

    Article  CAS  Google Scholar 

  21. Glaum, S. R. et al. Leptin, the Obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol. Pharmacol. 50, 230–235 (1996).

    CAS  PubMed  Google Scholar 

  22. Mercer, J. G. et al. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 387, 113–116 (1996).

    Article  CAS  Google Scholar 

  23. Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  Google Scholar 

  24. Woods, A. J. & Stock, M. J. Leptin activation in hypothalamus. Nature 381, 745 (1996).

    Article  ADS  CAS  Google Scholar 

  25. Elmquist, J. K., Ahima, R. S., Maratos-Flier, E., Flier, J. S. & Saper, C. B. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138, 839–842 (1997).

    Article  CAS  Google Scholar 

  26. Cusin, I., Rohner-Jeanrenaud, F., Sticker-Krongrad, A. & Jeanrenaud, B. The weight-reducing effect of an intracerebroventricular bolus injection of leptin in genetically obese fa/fa rats: reduced sensitivity compared with lean animals. Diabetes 45, 1446–1450 (1996).

    Article  CAS  Google Scholar 

  27. Seeley, R. J. et al. Intraventricular leptin reduces food intake and body weight of lean rats but not obese Zucker rats. Horm. Metab. Res. 28, 664–668 (1996).

    Article  CAS  Google Scholar 

  28. Keiffer, T. J., Heller, R. S., Leech, C. A., Holz, G. G. & Habener, J. F. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreating β-cells. Diabetes 26, 1087–1093 (1997).

    Google Scholar 

  29. Harvey, J., McKenna, F., Herson, P. S., Spanswick, D. & Ashford, M. L. J. Leptin activates ATP-sensitive potassium channels in the rat insulin secreting cell line, CRI-G1. J. Physiol. (Lond.) 504, 527–535 (1997).

    Article  CAS  Google Scholar 

  30. Lee, K., Rowe, I. C. M. & Ashford, M. L. J. Characterization of an ATP-modulated large conductance Ca2+-activated K+ channel present in rat cortical neurones. J. Physiol. (Lond.) 488, 319–337 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Todd for technical assistance. This work was supported by grants from the Wellcome Trust and Pharmacia-Upjohn.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, AB25 2ZD, Aberdeen, UK

    D. Spanswick, M. A. Smith, S. D. Logan & M. L. J. Ashford

  2. Pharmacia & Upjohn, 7000 Portage Road, Kalamazoo, 49001, Michigan, USA

    V. E. Groppi

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  1. D. Spanswick
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  2. M. A. Smith
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  4. S. D. Logan
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Correspondence to M. L. J. Ashford.

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Spanswick, D., Smith, M., Groppi, V. et al. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997). https://doi.org/10.1038/37379

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