title: Leptin promotes K(ATP) channel trafficking by AMPK signaling in pancreatic β-cells.
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 (K(ATP)) 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 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 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/calmodulin-dependent 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 K(ATP) 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 K(ATP) 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.
authors.affiliation: Cell Physiology Laboratory and Biomembrane Plasticity Research Center, Department of Physiology, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea.
authors.forename: Sun-Hyun
authors.initials: SH
authors.lastname: Park
authors.forename: Shin-Young
authors.initials: SY
authors.lastname: Ryu
authors.forename: Weon-Jin
authors.initials: WJ
authors.lastname: Yu
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Han
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Ji
authors.forename: Keunhee
authors.initials: K
authors.lastname: Oh
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.forename: Ajin
authors.initials: A
authors.lastname: Lim
authors.forename: Jae-Pyo
authors.initials: JP
authors.lastname: Jeon
authors.forename: Hyunsu
authors.initials: H
authors.lastname: Lee
authors.forename: Kyu-Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: Suk-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Ho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism*; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: D020738:Leptin; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D055372:AMP-Activated Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose