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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
Matson, C. A., Wiater, M. F. & Weigle, D. S. Leptin and the regulation of body adiposity. Diabetes Rev. 4, 488–508 (1996).
Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530–532 (1995).
Satoh, N. et al. The arcuate nucleus as a primary site of satiety effect of leptin in rats. Neurosci. Lett. 224, 149–152 (1997).
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).
Levin, B. E. & Routh, V. H. Role of the brain in energy balance and obesity. Am. J. Physiol. 40, R491–R500 (1996).
Zhang, Y. R. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Lee, G.-H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).
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).
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).
Oomura, Y., Ono, T., Ooyama, H. & Wayner, M. J. Glucose and osmosensitive neurones in the rat hypothalamus. Nature 222, 282–284 (1969).
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).
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).
Streamson, C. et al. Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr ). Diabetes 45, 1141–1143 (1996).
Phillips, M. S. et al. Leptin receptor missense mutation in the fatty Zucker rat. Nature Genet. 13, 18–19 (1996).
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).
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).
Treherne, J. M. & Ashford, M. L. J. Calcium-activated potassium channels in rat dissociated ventromedial hypothalamic neurones. J. Neuroendocrinol. 3, 323–329 (1991).
Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).
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).
Glaum, S. R. et al. Leptin, the Obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol. Pharmacol. 50, 230–235 (1996).
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).
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).
Woods, A. J. & Stock, M. J. Leptin activation in hypothalamus. Nature 381, 745 (1996).
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).
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).
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).
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).
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).
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).
Acknowledgements
We thank K. Todd for technical assistance. This work was supported by grants from the Wellcome Trust and Pharmacia-Upjohn.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/37379
This article is cited by
-
Hypothalamic Grb10 enhances leptin signalling and promotes weight loss
Nature Metabolism (2023)
-
Leptin and the endocrine control of energy balance
Nature Metabolism (2019)
-
Gpr17 deficiency in POMC neurons ameliorates the metabolic derangements caused by long-term high-fat diet feeding
Nutrition & Diabetes (2019)
-
Review of the role of the nervous system in glucose homoeostasis and future perspectives towards the management of diabetes
Bioelectronic Medicine (2018)
-
Leptin: role over central nervous system in epilepsy
BMC Neuroscience (2018)
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.