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/calmodulindependent 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.T he K ATP channel, an inwardly rectifying K + channel that consists of pore-forming Kir6.2 and regulatory sulfonylurea receptor 1 (SUR1) subunits (1), functions as an energy sensor: its gating is regulated mainly by the intracellular concentrations of ATP and ADP. In pancreatic β-cells, K ATP channels are inhibited or activated in response to the rise or fall in blood glucose levels, leading to changes in membrane excitability and insulin secretion (2, 3). Thus, K ATP channel gating has been considered an important mechanism in coupling blood glucose levels to insulin secretion. Recently, trafficking of K ATP channels to the plasma membrane was highlighted as another important mechanism for regulating K ATP channel activity (4-6).AMP-activated protein kinase (AMPK) is a key enzyme regulating energy homeostasis (7). We recently demonstrated that K ATP channels are recruited to the plasma membrane in glucosedeprived conditions via AMPK signaling in pancreatic β-cells (6). Inhibition of AMPK signaling significantly reduces K ATP currents, even after complete wash-out of intracellular ATP (6). Given these results, we proposed a model that recruitment of K ATP channels to the plasma membrane via AMPK signaling is crucial for K ATP channel activation in low-glucose conditions. However, the physiological relevance of this model remains unclear because pancreatic β-cells had to be incubated in media containing less than 3 mM glucose to recruit a sufficient number of K ATP channels to the plasma membrane (6). We thus hypothesized that there should be an e...

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…Leptin inhibits insulin secretion by increasing the cell-surface expression and the open probability of K ATP channels, resulting in a more hyperpolarized membrane potential (Holz et al, 2013). Leptin also induces an increased surface expression of Kv2.1 channels, leading to a rapid repolarization of membrane potential (Park et al, 2013b). These studies suggest that leptin exerts a coordinated trafficking regulation of K ATP and Kv2.1 channels to inhibit insulin secretion (Wu et al, 2015).…”

“…The mechanism by which leptin activates K ATP channels involves phosphatase and tensin homologe inhibition mediated by phosphoinositide 3 kinase. phosphatase and tensin homologe inhibition induces F-actin depolymerization and, consequently, K ATP channel opening (Park et al, 2013b;Wu et al, 2015).…”

KATPChannels in the Cardiovascular System

“…Many proteins pass through early endosomes in the recycling process. K ATP channels likely follow this route, as evidenced by the partial colocalization of internalized Kir6.2 in pancreatic ␤-cells with the early endosome antigen 1 (EEA1) protein, which serves as a marker for this cellular compartment (632). The term early endosome actually refers to two types of endosomes, namely, the sorting endosome and the endocytic recycling compartment (ERC) (549).…”

The Roles of Rasd1 small G proteins and leptin in the activation of TRPC4 transient receptor potential channels

“…18 Similar study regarding leptin and glucose regulation of TRPC4 was recently published. 19 In this study, leptin is shown to activate TRPC4 channel and Ca 2C influx through TRPC4 activates AMPK that triggers translocation of ATPdependent K C channel (KATP) to the plasma membrane to hyperpolarize the resting membrane potential in pancreatic b-cell. Leptin activates TRPC4 in POMC, 20,21,22 and kisseptinsecreting hypothalamic neuron.…”

“…The finding of TRPC4 current in pancreatic b-cell in response to dexamethasone was interesting since similar study regarding leptin and glucose regulation of TRPC4 was recently published. 19 Leptin was first discovered in 1994 by Zang et al 59 and it is the most important and widely studied hormones in the control of energy balance. 60 Leptin is a 16 kDa protein mostly secreted from adipose tissue which has a critical role regulating body weight and energy homeostasis.…”