| First Author | Park SH | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 31 | Pages | 12673-8 |
| PubMed ID | 23858470 | Mgi Jnum | J:198774 |
| Mgi Id | MGI:5499216 | Doi | 10.1073/pnas.1216351110 |
| Citation | Park SH, et al. (2013) Leptin promotes KATP channel trafficking by AMPK signaling in pancreatic beta-cells. Proc Natl Acad Sci U S A 110(31):12673-8 |
| abstractText | 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 beta-cells. In this study, we provide evidence that leptin modulates pancreatic beta-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 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 KATP 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 KATP 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. |
