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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: Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 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.

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 mIPSCsA) Representative recording traces showing mIPSCs recorded from POMC neurons in the presence of TTX (1 µM). Treatment with leptin (100 nM) increased mIPSC frequency in a subset of POMC neurons at 2.5, 5 and 10 mM glucose. HP = −70mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of mIPSCs from individual POMC neurons before and after treatment with leptin (Bold line: total mean change in mIPSC frequency; 2.5 mM, n = 20 neurons; 5 mM, n = 21 neurons; 10 mM, n = 31 neurons). C: control, L: leptinC) Pooled data showing mIPSC amplitude. Both superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin did not change the mean amplitude of mIPSCs (2.5 mM: n=20 neurons; 5 mM: n=21 neurons; 10 mM: n = 31 neurons). Scale bar: 20 pA, 20 ms.**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
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Figure 2: Two distinct effects of leptin on mIPSCsA) Representative recording traces showing mIPSCs recorded from POMC neurons in the presence of TTX (1 µM). Treatment with leptin (100 nM) increased mIPSC frequency in a subset of POMC neurons at 2.5, 5 and 10 mM glucose. HP = −70mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of mIPSCs from individual POMC neurons before and after treatment with leptin (Bold line: total mean change in mIPSC frequency; 2.5 mM, n = 20 neurons; 5 mM, n = 21 neurons; 10 mM, n = 31 neurons). C: control, L: leptinC) Pooled data showing mIPSC amplitude. Both superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin did not change the mean amplitude of mIPSCs (2.5 mM: n=20 neurons; 5 mM: n=21 neurons; 10 mM: n = 31 neurons). Scale bar: 20 pA, 20 ms.**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.

Mentions: In the presence of tetrodotoxin (TTX; 1µM) to block the neuronal network activity, treatment with leptin increased the frequency of miniature IPSCs (mIPSCs) at 2.5 and 5 mM glucose (Fig. 2A, B and Table 1). Only a few POMC neurons responded to leptin with reduced mIPSC frequency (Fig. 2B and Table 1). Unlike the situation at 2.5 and 5 mM glucose, leptin either enhanced or reduced mIPSC frequency in POMC neurons at 10 mM glucose (Fig 2A and B). Leptin had no effect on mIPSC amplitude (Fig. 2C). There was no difference in the baseline mIPSC frequency under these conditions ([glucose] 2.5 mM, 1.1 ± 0.2 Hz; 5 mM, 1.4 ± 0.3 Hz; 10 mM, 1.4 ± 0.2 Hz; n = 20, 21, and 31 neurons, respectively).


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 mIPSCsA) Representative recording traces showing mIPSCs recorded from POMC neurons in the presence of TTX (1 µM). Treatment with leptin (100 nM) increased mIPSC frequency in a subset of POMC neurons at 2.5, 5 and 10 mM glucose. HP = −70mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of mIPSCs from individual POMC neurons before and after treatment with leptin (Bold line: total mean change in mIPSC frequency; 2.5 mM, n = 20 neurons; 5 mM, n = 21 neurons; 10 mM, n = 31 neurons). C: control, L: leptinC) Pooled data showing mIPSC amplitude. Both superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin did not change the mean amplitude of mIPSCs (2.5 mM: n=20 neurons; 5 mM: n=21 neurons; 10 mM: n = 31 neurons). Scale bar: 20 pA, 20 ms.**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
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Figure 2: Two distinct effects of leptin on mIPSCsA) Representative recording traces showing mIPSCs recorded from POMC neurons in the presence of TTX (1 µM). Treatment with leptin (100 nM) increased mIPSC frequency in a subset of POMC neurons at 2.5, 5 and 10 mM glucose. HP = −70mV. Scale bar: 100 pA, 10 s.B) Graphs showing normalized frequency of mIPSCs from individual POMC neurons before and after treatment with leptin (Bold line: total mean change in mIPSC frequency; 2.5 mM, n = 20 neurons; 5 mM, n = 21 neurons; 10 mM, n = 31 neurons). C: control, L: leptinC) Pooled data showing mIPSC amplitude. Both superimposition of traces of sIPSCs before (blue) and after (red) application of leptin. Leptin did not change the mean amplitude of mIPSCs (2.5 mM: n=20 neurons; 5 mM: n=21 neurons; 10 mM: n = 31 neurons). Scale bar: 20 pA, 20 ms.**p < 0.01, ***p < 0.001 vs. control (paired t-test). All data are shown as mean ± SEM.
Mentions: In the presence of tetrodotoxin (TTX; 1µM) to block the neuronal network activity, treatment with leptin increased the frequency of miniature IPSCs (mIPSCs) at 2.5 and 5 mM glucose (Fig. 2A, B and Table 1). Only a few POMC neurons responded to leptin with reduced mIPSC frequency (Fig. 2B and Table 1). Unlike the situation at 2.5 and 5 mM glucose, leptin either enhanced or reduced mIPSC frequency in POMC neurons at 10 mM glucose (Fig 2A and B). Leptin had no effect on mIPSC amplitude (Fig. 2C). There was no difference in the baseline mIPSC frequency under these conditions ([glucose] 2.5 mM, 1.1 ± 0.2 Hz; 5 mM, 1.4 ± 0.3 Hz; 10 mM, 1.4 ± 0.2 Hz; n = 20, 21, and 31 neurons, respectively).

Bottom Line: Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 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.

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