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Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

Bottom Line: Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important.Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus

Two distinct effects of leptin on sIPSCsA) Representative recording traces showing sIPSCs recorded from POMC neurons at different glucose levels. Addition of leptin (100 nM) robustly increased sIPSC frequency at 2.5 mM glucose, whereas leptin had an inhibitory effect on sIPSCs at 10 mM glucose. HP = −70 mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of sIPSCs from individual POMC neurons before and after treatment with leptin (100 nM) at different glucose levels (Bold line: total mean change in sIPSC frequency; 2.5 mM, n = 19 neurons; 5 mM, n = 27 neurons; 10 mM, n = 26 neurons). C: control, L: leptinC) Pooled data showing sIPSC amplitude. Superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin increased the mean amplitude of sIPSCs at 2.5 mM glucose (2.5 mM: n = 19 neurons; 5 mM: n = 27 neurons; 10 mM: n = 26 neurons). Scale bar: 20 pA, 20 ms.*p < 0.05, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
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Figure 1: Two distinct effects of leptin on sIPSCsA) Representative recording traces showing sIPSCs recorded from POMC neurons at different glucose levels. Addition of leptin (100 nM) robustly increased sIPSC frequency at 2.5 mM glucose, whereas leptin had an inhibitory effect on sIPSCs at 10 mM glucose. HP = −70 mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of sIPSCs from individual POMC neurons before and after treatment with leptin (100 nM) at different glucose levels (Bold line: total mean change in sIPSC frequency; 2.5 mM, n = 19 neurons; 5 mM, n = 27 neurons; 10 mM, n = 26 neurons). C: control, L: leptinC) Pooled data showing sIPSC amplitude. Superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin increased the mean amplitude of sIPSCs at 2.5 mM glucose (2.5 mM: n = 19 neurons; 5 mM: n = 27 neurons; 10 mM: n = 26 neurons). Scale bar: 20 pA, 20 ms.*p < 0.05, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.

Mentions: This report is based on recordings from approximately 500 neurons in acute hypothalamus slices from both male and female animals. We examined whether alterations in extracellular glucose levels influenced leptin’s action on spontaneous GABAergic inhibitory currents (sIPSCs) to POMC neurons. As described in the prior studies28, 29, leptin (100 nM) significantly depressed GABAergic transmission in a subset of POMC neurons at 10 mM glucose, consistent with a prior study28 (Fig. 1A, B and Table 1; mean percent change in spontaneous inhibitory postsynaptic currents (sIPSCs) frequency: 60.3 ± 4.9 % of control; n = 11 out of 26 neurons). Treatment with leptin significantly reduced the mean frequency without altering the mean amplitude of sIPSCs (Fig. 1C and Table 1).


Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

Lee DK, Jeong JH, Chun SK, Chua S, Jo YH - Nat Commun (2015)

Two distinct effects of leptin on sIPSCsA) Representative recording traces showing sIPSCs recorded from POMC neurons at different glucose levels. Addition of leptin (100 nM) robustly increased sIPSC frequency at 2.5 mM glucose, whereas leptin had an inhibitory effect on sIPSCs at 10 mM glucose. HP = −70 mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of sIPSCs from individual POMC neurons before and after treatment with leptin (100 nM) at different glucose levels (Bold line: total mean change in sIPSC frequency; 2.5 mM, n = 19 neurons; 5 mM, n = 27 neurons; 10 mM, n = 26 neurons). C: control, L: leptinC) Pooled data showing sIPSC amplitude. Superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin increased the mean amplitude of sIPSCs at 2.5 mM glucose (2.5 mM: n = 19 neurons; 5 mM: n = 27 neurons; 10 mM: n = 26 neurons). Scale bar: 20 pA, 20 ms.*p < 0.05, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
© Copyright Policy
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Show All Figures
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Figure 1: Two distinct effects of leptin on sIPSCsA) Representative recording traces showing sIPSCs recorded from POMC neurons at different glucose levels. Addition of leptin (100 nM) robustly increased sIPSC frequency at 2.5 mM glucose, whereas leptin had an inhibitory effect on sIPSCs at 10 mM glucose. HP = −70 mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of sIPSCs from individual POMC neurons before and after treatment with leptin (100 nM) at different glucose levels (Bold line: total mean change in sIPSC frequency; 2.5 mM, n = 19 neurons; 5 mM, n = 27 neurons; 10 mM, n = 26 neurons). C: control, L: leptinC) Pooled data showing sIPSC amplitude. Superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin increased the mean amplitude of sIPSCs at 2.5 mM glucose (2.5 mM: n = 19 neurons; 5 mM: n = 27 neurons; 10 mM: n = 26 neurons). Scale bar: 20 pA, 20 ms.*p < 0.05, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
Mentions: This report is based on recordings from approximately 500 neurons in acute hypothalamus slices from both male and female animals. We examined whether alterations in extracellular glucose levels influenced leptin’s action on spontaneous GABAergic inhibitory currents (sIPSCs) to POMC neurons. As described in the prior studies28, 29, leptin (100 nM) significantly depressed GABAergic transmission in a subset of POMC neurons at 10 mM glucose, consistent with a prior study28 (Fig. 1A, B and Table 1; mean percent change in spontaneous inhibitory postsynaptic currents (sIPSCs) frequency: 60.3 ± 4.9 % of control; n = 11 out of 26 neurons). Treatment with leptin significantly reduced the mean frequency without altering the mean amplitude of sIPSCs (Fig. 1C and Table 1).

Bottom Line: Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important.Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose.However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

ABSTRACT
Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

No MeSH data available.


Related in: MedlinePlus