Leptin promotes K-ATP channel trafficking by AMPK signaling in pancreatic beta-cells

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Leptin is a pivotal regulator of energy and glucose homeostasis, and defects in leptin signaling result in obesity and diabetes. The ATP-sensitive potassium (K-ATP) channels couple glucose metabolism to insulin secretion in pancreatic beta-cells. In this study, we provide evidence that leptin modulates pancreatic beta-cell functions by promoting K-ATP channel translocation to the plasma membrane via AMP-activated protein kinase (AMPK) signaling. K-ATP channels were localized mostly to intracellular compartments of pancreatic beta-cells in the fed state and translocated to the plasma membrane in the fasted state. This process was defective in leptin-deficient ob/ob mice, but restored by leptin treatment. We discovered that the molecular mechanism of leptin-induced AMPK activation involves canonical transient receptor potential 4 and calcium/calmodulin-dependent protein kinase kinase beta. AMPK activation was dependent on both leptin and glucose concentrations, so at optimal concentrations of leptin, AMPK was activated sufficiently to induce K-ATP channel trafficking and hyperpolarization of pancreatic beta-cells in a physiological range of fasting glucose levels. There was a close correlation between phospho-AMPK levels and beta-cell membrane potentials, suggesting that AMPK-dependent K-ATP channel trafficking is a key mechanism for regulating beta-cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating beta-cell excitability.
Publisher
NATL ACAD SCIENCES
Issue Date
2013-07
Language
English
Article Type
Article
Keywords

ACTIVATED PROTEIN-KINASE; INSULIN-SECRETION; METABOLISM; RECEPTOR; TRPC5; SENSITIVITY; WEIGHT; ENERGY; MICE; RAT

Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.110, no.31, pp.12673 - 12678

ISSN
0027-8424
DOI
10.1073/pnas.1216351110
URI
http://hdl.handle.net/10203/201584
Appears in Collection
BS-Journal Papers(저널논문)
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