N Yua,b, Young Eun Hana,b, Young-Sun Jia,b, Keunhee Ohc, Jong-Woo Sohna, Ajin Lima, Jae-Pyo Jeonb, Hyunsu Leea,b, Kyu-Hee Leea,b, Suk-Ho Leea,b, Per-Olof Berggrend,e, Ju-Hong Jeonb,1, and Won-Kyung Hoa,b,a Cell Physiology Laboratory and Biomembrane Plasticity Study Center, bDepartment of Physiology, and cDepartment of Biomedical Science and Transplantation Investigation Institute, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea; dThe Rolf Luft Study Center for Diabetes and Endocrinology, Karolinska Institutet, 171 76 Stockholm, Sweden; and eDivision of Integrative Biosciences and Biotechnology, Pohang University of Science and Technologies, Pohang 790-784, Republic of KoreaEdited by Lily Yeh Jan, University of California, San Francisco, CA, and approved June 21, 2013 (received for overview September 24, 2012)Leptin is usually a pivotal regulator of power and glucose homeostasis, and defects in leptin signaling lead to obesity and diabetes. The ATP-sensitive potassium (KATP) channels couple glucose metabolism to insulin secretion in pancreatic -cells. Within this study, we deliver proof that leptin modulates pancreatic -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 -cells within the fed state and translocated for the plasma membrane inside the fasted state. This procedure was defective in leptin-deficient ob/ob mice, but restored by leptin treatment. We discovered that the molecular mechanism of leptin-induced AMPK activation includes canonical transient receptor possible 4 and calcium/calmodulindependent protein kinase kinase . 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 GPR84 Source hyperpolarization of pancreatic -cells in a physiological range of fasting glucose levels. There was a close correlation among phospho-AMPK levels and -cell membrane potentials, suggesting that AMPK-dependent KATP channel trafficking is often a important mechanism for regulating -cell membrane potentials. Our results present a signaling pathway whereby leptin regulates glucose homeostasis by modulating -cell excitability.to its central action, leptin regulates the release of insulin and glucagon, the essential hormones regulating glucose homeostasis, by direct actions on – and -cells of pancreatic islets, respectively (ten?two). It thus was proposed that the adipoinsular axis is critical for preserving nutrient balance and that dysregulation of this axis contributes to obesity and diabetes (12). On the other hand, intracellular signaling mechanisms underlying leptin effects are largely unknown. Leptin was shown to improve KATP currents in pancreatic -cells (13, 14), however the possibility that KATP channel trafficking Bcl-2 Family Activator list mediates leptin-induced KATP channel activation has not been explored. Within the present study, we demonstrate that the surface levels of KATP channels raise in pancreatic -cells beneath fasting conditions in vivo. Translocation of KATP channels for the plasma membrane in fasting was absent in pancreatic -cells from ob/ob mice, but restored by therapy with leptin, suggesting a part for leptin in KATP channel trafficking in vivo. We further show that leptin-induced AMPK activation, which is essential for KATP channel trafficking for the plasma membrane, is mediated by activation.
