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

Dong Kun Lee,Jae Hoon Jeong,Streamson Chua,Sung-Kun Chun,Young-Hwan Jo

doi:10.1038/ncomms7618

Dong Kun Lee, Jae Hoon Jeong + Show 3 more

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https://doi.org/10.1038/ncomms7618

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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 signaling 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 signaling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

Highlights

Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis
Activation of TRPC channels is mediated by the janus kinase 2 (JAK2)–phosphatidylinositide 3-kinases (PI3K)– phospholipase C (PLC) pathway[15]
The JAK2–signal transducer and activator of transcription 3 (STAT3) pathway contributes to the regulation of long-term energy homeostasis via the transcription of POMC and the inhibitory suppressor of cytokine signalling 3, the JAK2–PI3K pathway appears to be important in the regulation of POMC neuron activity, resulting in leptin-induced hypophagia

Summary

Introduction

Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. 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. Activation of TRPC channels is mediated by the janus kinase 2 (JAK2)–phosphatidylinositide 3-kinases (PI3K)– phospholipase C (PLC) pathway[15] This JAK2–PI3K–PLC pathway in POMC neurons plays an essential role in the regulation of energy and glucose homeostasis. Disruption of PI3K in POMC neurons blunts leptin’s action on the membrane potential as well as food intake, mice show normal long-term body weight regulation[17] This is further supported by the study showing that mice deficient of the p110b isoform of PI3K in POMC neurons exhibit leptin resistance, increased adiposity and increased food intake, associated with no electrical response to leptin[18]. GABAergic synapses at POMC neurons integrate glucose and leptin signalling, and this integration is subject to modulation by high-fat feeding

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