Leptin promotes KATP channel trafficking by AMPK signaling in pancreatic β-cells

Sun Hyun Park, Shin Young Ryu, Weon Jin Yu, Young Eun Han, Young Sun Ji, Keunhee Oh, Jong Woo Sohn, Ajin Lim, Jae Pyo Jeon, Hyunsu Lee, Kyu Hee Lee, Suk Ho Lee, Per Olof Berggren, Ju Hong Jeon, Won Kyung Ho

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Leptin is a pivotal regulator of energy and glucose homeostasis, and defects in leptin signaling result in obesity and diabetes. The ATP-sensitive potassium (KATP) channels couple glucose metabolism to insulin secretion in pancreatic β-cells. In this study, we provide evidence that leptin modulates pancreatic β-cell functions by promoting KATP channel translocation to the plasma membrane via AMP-activated protein kinase (AMPK) signaling. KATP channels were localized mostly to intracellular compartments of pancreatic β-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/ calmodulindependent protein kinase kinase β. AMPK activation was dependent on both leptin and glucose concentrations, so at optimal concentrations of leptin, AMPK was activated sufficiently to induce KATP channel trafficking and hyperpolarization of pancreatic β-cells in a physiological range of fasting glucose levels. There was a close correlation between phospho-AMPK levels and β-cell membrane potentials, suggesting that AMPK-dependent KATP channel trafficking is a key mechanism for regulating β-cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating β-cell excitability.

Original languageEnglish (US)
Pages (from-to)12673-12678
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number31
DOIs
StatePublished - Jul 30 2013

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Leptin promotes K<sub>ATP</sub> channel trafficking by AMPK signaling in pancreatic β-cells'. Together they form a unique fingerprint.

Cite this