Leptin and insulin stimulation of signalling pathways in arcuate nucleus neurones: PI3K dependent actin reorganization and KATPchannel activation
Open accessAbstract
Background: Leptin and insulin are long-term regulators of body weight. They act in hypothalamic centres to modulate the function of specific neuronal subtypes, by altering transcriptional control of releasable peptides and by modifying neuronal electrical activity. A key cellular signalling intermediate, implicated in control of food intake by these hormones, is the enzyme phosphoinositide 3-kinase. In this study we have explored further the linkage between this enzyme and other cellular mediators of leptin and insulin action on rat arcuate nucleus neurones and the mouse hypothalamic cell line, GT1-7. Results: Leptin and insulin increased the levels of various phosphorylated signalling intermediates, associated with the JAK2-STAT3, MAPK and PI3K cascades in the arcuate nucleus. Inhibitors of PI3K were shown to reduce the hormone driven phosphorylation through the PI3K and MAPK pathways. Using isolated arcuate neurones, leptin and insulin were demonstrated to increase the activity of K ATP channels in a PI3K dependent manner, and to increase levels of PtdIns(3,4,5)P 3. K ATP activation by these hormones in arcuate neurones was also sensitive to the presence of the actin filament stabilising toxin, jasplakinolide. Using confocal imaging of fluorescently labelled actin and direct analysis of G- and F-actin concentration in GT1-7 cells, leptin was demonstrated directly to induce a re-organization of cellular actin, by increasing levels of globular actin at the expense of filamentous actin in a PI3-kinase dependent manner. Leptin stimulated PI3-kinase activity in GT1-7 cells and an increase in PtdIns(3,4,5)P 3 could be detected, which was prevented by PI3K inhibitors. Conclusions: Leptin and insulin mediated phosphorylation of cellular signalling intermediates and of K ATP channel activation in arcuate neurones is sensitive to PI3K inhibition, thus strengthening further the likely importance of this enzyme in leptin and insulin mediated energy homeostasis control. The sensitivity of leptin and insulin stimulation of K ATP channel opening in arcuate neurones to jasplakinolide indicates that cytoskeletal remodelling may be an important contributor to the cellular signalling mechanisms of these hormones in hypothalamic neurones. This hypothesis is reinforced by the finding that leptin induces actin filament depolymerization, in a PI3K dependent manner in a mouse hypothalamic cell line.
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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).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [116]
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“Initial support for this hypothesis was provided by electrophysiological studies in which leptin and insulin were shown to hyperpolarize a subset of “glucoseresponsive” 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,…”
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- Authors
- Mirshamsi, S., Laidlaw, H. A., Ning, K., Anderson, E., Burgess, L. A., Gray, A., Sutherland, C., & Ashford, M. L.
- Affiliations
- University of Dundee (GB)
- Corresponding author
- Ashford, Michael LJ
- Venue
- BMC Neuroscience
- Published
- 2004-12-06
- Volume
- 5
- Issue
- 1
- Pages
- 54-54
- ISSN
- 1471-2202 (ISSN-L)
- PMC
- PMC539348
- OpenAlex
- W1757645550
- Cited by
- 173
- References
- 56
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 2 · 2018: 4 · 2017: 6 · 2016: 8 · 2015: 11 · 2014: 7 · 2013: 7 · 2012: 11
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- BMC Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Wellcome Trust (068692)
- Tenovus
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin, insulin, arcuate nucleus, hypothalamus, PI3K signaling, actin reorganization, ATP-sensitive potassium channels, phosphatidylinositol 3,4,5-trisphosphate, jasplakinolide, MAPK signaling, JAK2/STAT3 signaling, food intake regulation, energy homeostasis, cytoskeletal remodeling, GT1-7 cells
- MeSH terms
- Adenosine Triphosphate, Animals, Arcuate Nucleus of Hypothalamus, Cell Line, Cells, Cultured, Insulin, Male, Actin Cytoskeleton, Neurons, Phosphorylation, Potassium Channels, Signal Transduction, Rats, Sprague-Dawley, Patch-Clamp Techniques, Phosphatidylinositol 3-Kinases, Leptin, Mice, Rats
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