Leptin activates PKA via a novel mechanism to regulate KATP channel trafficking in pancreatic β‐cells

Abstract

The adipocyte hormone leptin has a well‐established role in energy homeostasis via its actions in the central nervous system. In addition, leptin has been shown to have direct actions on peripheral tissues. In pancreatic β‐cells leptin inhibits insulin secretion by increasing conductance of ATP‐sensitive potassium (KATP) channels, which causes membrane hyperpolarization and reduces β‐cell electrical activity. There is evidence that disrupting leptin signaling at the β‐cell level may lead to excessive insulin secretion and contribute to insulin resistance and eventually type 2 diabetes. Recent studies have shown that leptin promotes KATP channel trafficking to increase KATP channel surface density and thereby KATP conductance in β‐cells. We found that leptin triggers a signaling pathway that involves potentiation of NMDA receptors, leading to an influx of calcium and activation of CaMKKβ, which then phosphorylates and activates AMPK; downstream of AMPK actin remodeling occurs in a PKA‐dependent manner that allows vesicles containing KATP channels to traffic to the β‐cell membrane. A knowledge gap in this pathway is whether PKA plays a permissive role or whether leptin signaling that results in AMPK activation leads to increased PKA activity for actin remodeling. Here we implement a FRET‐based PKA activity reporter to show that leptin signaling does indeed increase PKA activity and that this occurs via the NMDAR‐CaMKKβ‐AMPK signaling axis. Moreover, we provide evidence that the ability of leptin to regulate KATP channel trafficking requires that PKA is anchored to PKA anchoring proteins (AKAPs). AKAPs are scaffolding proteins known to organize signaling complexes for localized PKA signaling. Our results suggest that leptin signaling in β‐cells may be localized via a signaling complex involving AKAP to achieve spatiotemporal specificity. Additional studies into AKAP‐mediated organization of leptin signaling molecules in β‐cells will likely provide insight as to how leptin signaling may be disrupted in pathophysiological states such as type 2 diabetes.Support or Funding InformationNIH grant R01 DK57699 to SLS