Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion

Cochrane, Veronica A.; Shyng, Show Ling

doi:10.3390/ijms20112660

Cited by 11 publications

(7 citation statements)

References 79 publications

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“…These factors are involved in numerous biological processes, including glucose and lipid metabolism, food intake, inflammation, coagulation, and the maintenance of metabolic homeostasis [ 13 ]. Significantly, many of these adipokines and FFAs might directly influence numerous aspects of β-cell function and viability, including insulin synthesis and secretion as well as β-cell apoptosis and proliferation [ 14 , 15 , 16 ]. Evidence suggests that the cross-talk between AT and pancreatic β-cells is bidirectional and could drive the maintenance of the β-cell functional mass under physiological conditions [ 17 , 18 ].…”

Section: Adipose Tissue/β-cell Cross-talk: a Bidirectional Communicationmentioning

confidence: 99%

“…Interestingly, many of these adipokines might directly influence numerous aspects of β-cell function and viability, including insulin synthesis and secretion, as well as β-cell apoptosis and proliferation [ 14 , 15 , 16 ]. Therefore, it is to be expected that alterations in the levels of these adipokines could contribute to the reduction in the β-cell functional mass, which is chiefly responsible for the onset of T2D.…”

Section: Dysfunctional Adipose Tissue In Obesity: Alteration Of the A...mentioning

confidence: 99%

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Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Biondi

Marrano

Borrelli

et al. 2022

IJMS

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The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass.

show abstract

Section: Adipose Tissue/β-cell Cross-talk: a Bidirectional Communicationmentioning

confidence: 99%

Section: Dysfunctional Adipose Tissue In Obesity: Alteration Of the A...mentioning

confidence: 99%

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Biondi

Marrano

Borrelli

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…Studies into the mechanisms by which leptin regulates KATP and Kv2.1 channel trafficking so far have identified several key molecular players. These include the NMDA subtype glutamate receptors (NMDARs), calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), AMPK and PKA (15). Evidence that has emerged reveals a novel signaling pathway wherein leptin potentiates NMDAR function to increase Ca 2+ influx, resulting in activation of CaMKKβ, which phosphorylates and activates AMPK; AMPK in turn causes PKA-dependent actin depolymerization, culminating in increased trafficking of KATP and Kv2.1 channels to the βcell surface.…”

Section: Introductionmentioning

confidence: 99%

Leptin modulates pancreatic β-cell membrane potential through Src kinase–mediated phosphorylation of NMDA receptors

Cochrane

Yang

et al. 2020

Journal of Biological Chemistry

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The adipocyte-derived hormone leptin increases trafficking of KATP and Kv2.1 channels to the pancreatic β-cell surface, resulting in membrane hyperpolarization and suppression of insulin secretion. We have previously shown that this effect of leptin is mediated by the NMDA subtype of glutamate receptors (NMDARs). It does so by potentiating NMDAR activity, thus enhancing Ca2+ influx and the ensuing downstream signaling events that drive channel trafficking to the cell surface. However, the molecular mechanism by which leptin potentiates NMDARs in β-cells remains unknown. Here we report that leptin augments NMDAR function via Src kinase-mediated phosphorylation of the GluN2A subunit. Leptin-induced membrane hyperpolarization diminished upon pharmacological inhibition of GluN2A but not GluN2B, indicating involvement of GluN2A-containing NMDARs. GluN2A harbors tyrosine residues which when phosphorylated by Src family kinases potentiate NMDAR activity. We found that leptin increases phosphorylation of Y418 in Src, an indicator of kinase activation. Pharmacological inhibition of Src or overexpression of a kinase-dead Src mutant prevented the effect of leptin, while a Src kinase activator peptide mimicked it. Using mutant GluN2A overexpression, we show that Y1292 and Y1387 but not Y1325 are responsible for the effect of leptin. Importantly, β-cells from db/db mice, a type 2 diabetes mouse model lacking functional leptin receptors, or from obese diabetic human donors failed to respond to leptin but hyperpolarized in response to NMDA. Our study reveals a signaling pathway wherein leptin modulates NMDARs via Src to regulate β-cell excitability and suggests NMDARs as a potential target to overcome leptin resistance.

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“…37,38 These channels contribute to the resting membrane potential and excitability in various types of cells, such as dorsal root ganglion neurons, 39 hippocampal dentate gyrus neurons 40 and pancreatic β-cells. 41 An increase in K-ATP channel conductance decreases both the resting membrane potential and excitability in neurons. Thus, we tested whether the oxytocin-induced reduction in mitral-cell excitability is mediated by K-ATP channels.…”

Section: Oxytocin Reduces the Excitability Of Mitral Cells Via Modumentioning

confidence: 99%

Oxytocin modulates neural processing of mitral/tufted cells in the olfactory bulb

Sun

Yin

et al. 2021

Acta Physiologica

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Aim Oxytocin plays an important role in social recognition in rodents, which is mediated predominantly by the olfactory system. Although oxytocin modulates neural activity in the olfactory bulb, the underlying mechanism is largely unknown. Here, we studied how direct infusion of oxytocin into the olfactory bulb affect social interactions in mice and modulate the neural activity of mitral/tufted cells in the olfactory bulb. Methods A three‐chamber social interaction test was used in the behavioural test. For in vivo studies, single unit recordings, local field potential recordings and fibre photometry recordings were used to record the neural activity of olfactory bulb. For in vitro studies, we performed patch clamp recordings in the slice of the olfactory bulb. Results Behaviourally, direct oxytocin infusion in olfactory bulb increased performance in a social interaction task. Moreover, odour‐evoked responses of mitral/tufted cells and neural discrimination of odours were both enhanced by oxytocin, whereas the spontaneous firing rate of mitral/tufted cells was reduced. At the neural network level, oxytocin decreased the amplitude of odour‐evoked high gamma responses. At the cell population level, oxytocin decreased odour‐evoked calcium responses (reflecting neural activity) specifically in granule cells. Moreover, in vitro slice recordings revealed that the inhibitory effect of oxytocin on mitral cell activity is mediated mainly by modulation of ATP‐sensitive potassium channels and involves the oxytocin receptor–Gq–PLC–IP3 signalling pathway. Conclusion Oxytocin modulates social interaction, likely by increasing the signal‐to‐noise ratio of odour responses in mitral cells which is partly through ATP‐sensitive potassium channel.

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Leptin-induced Trafficking of KATP Channels: A Mechanism to Regulate Pancreatic β-cell Excitability and Insulin Secretion

Cited by 11 publications

References 79 publications

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

Leptin modulates pancreatic β-cell membrane potential through Src kinase–mediated phosphorylation of NMDA receptors

Oxytocin modulates neural processing of mitral/tufted cells in the olfactory bulb

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