Leptin regulates surface expression of β ‐cell ATP‐sensitive potassium channels via an AMPK/PKA/Cofilin signaling cascade

An adipoinsular axis is a dual hormonal feedback loop in which insulin produced by pancreatic β‐cells increases leptin production from adipose tissue and leptin released from adipose tissue in turn down regulates insulin secretion. Leptin has been shown to reduce insulin secretion at least in part by increasing K ATP channel conductance, a key regulator of β‐cell membrane potential in response to glucose metabolism. However, the mechanism by which leptin increases K ATP currents is unknown. We report here that leptin increases K ATP channel expression in the β‐cell plasma membrane. Using a combination of pharmacological and molecular genetics approach, we show that this effect is mediated by a signaling cascade involving activation of AMPK via phosphorylation at Thr‐172 and activation of PKA, which then leads to phoshorylation of the actin binding protein cofilin and actin depolymerization. Imaging and surface biotinylation pulsechase experiments show that increased surface K ATP channel abundance in response to leptin is primarily a consequence of increased K ATP channel trafficking to the cell surface and that this trafficking event is tightly correlated with actin depolymerization. Taken together, our findings suggested that leptin inhibit insulin secretion by recruiting K ATP channels to the β‐cell plasma membrane via a AMPK/PKA/cofiln/F‐actin depolymerization signaling mechanism. (This work was supported by NIDDK057699.)