Cited by 628Regulation of Appetite and ObesityIon channel regulation and functionAdipokines, Inflammation, and Metabolic Diseases

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

Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., Ashford, M. L. J.·1997·Nature

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 weight. It has been proposed that leptin acts in the hypothalamus, the main control centre for satiety and energy expenditure. Mutations in leptin or the receptor isoform (Ob-R[L]) present in hypothalamic neurons result in profound obesity and symptoms of non-insulin-dependent diabetes. 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 (K[ATP]) channel. Our data indicate that the K(ATP) channel may function as the molecular end-point of the pathway following leptin activation of the Ob-R(L) receptor in hypothalamic neurons.

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Crossref · 10.1038/37379

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29 of 29 references verified0 citation errors · 0 not checkable

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  • Leptin rapidly changes the membrane potential and firing rate of hypothalamic neurons in electrophysiological studies.

    “in electrophysiological studies using freshly prepared hypothalamic slices, leptin rapidly changes the membrane potential and firing rate of neurons (42, 176)”
  • Leptin and insulin hyperpolarize a subset of glucose-responsive neurons in the ARC via activation of KATP channels, a mechanism blocked by a PI3K inhibitor.

    “leptin and insulin were shown to hyperpolarize a subset of “glucose-responsive” neurons in the ARC via activation of the ATP-sensitive potassium channel (KATP) (176, 177) via a mechanism that was blocked by a PI3K inhibitor (116, 177).”
  • Insulin and leptin activate ATP-sensitive potassium channels and hyperpolarize a subset of glucose-responsive neurons via a mechanism requiring PI3K.

    “both insulin and leptin activate ATP-sensitive potassium channels and thereby hyperpolarize a subset of “glucose-responsive” neurons via a mechanism that requires PI3K (176, 177).”

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Authors
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D., & Ashford, M. L. J.
Affiliations
University of Aberdeen (GB)
Corresponding author
Ashford, M. L. J.
Venue
Nature
Published
1997-12
Volume
390
Issue
6659
Pages
521-525
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W1623365227
Cited by
628
References
29
Citations by year
2026: 6 · 2025: 3 · 2024: 5 · 2023: 9 · 2022: 6 · 2021: 13 · 2020: 10 · 2019: 9 · 2018: 16 · 2017: 17 · 2016: 9 · 2015: 15 · 2014: 22 · 2013: 21 · 2012: 26
FWCI
9.11
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Wellcome Trust
  • University of Aberdeen
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
leptin, ATP-sensitive potassium channels, hypothalamic neurons, glucose receptor, neuronal hyperpolarization, potassium currents, tolbutamide, sulfonylureas, obesity, Zucker rats, food intake regulation, satiety, energy expenditure
MeSH terms
Adenosine Triphosphate, Animals, Cell Membrane, Electrophysiology, Glucose, Hypoglycemic Agents, Hypothalamus, Neurons, Obesity, Proteins, Rats, Zucker, Tolbutamide, Potassium Channels, Rats, Sprague-Dawley, Leptin, Rats, In Vitro Techniques

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