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.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
AMP-Activated Protein Kinases / drug effects
-
Animals
-
Blood Glucose / metabolism*
-
Brain / drug effects
-
Diet, High-Fat
-
GABAergic Neurons / drug effects*
-
GABAergic Neurons / metabolism
-
Glucose
-
Homeostasis
-
Janus Kinase 2 / drug effects
-
Leptin / metabolism
-
Leptin / pharmacology*
-
Mice
-
Mice, Transgenic
-
Neural Inhibition / drug effects
-
Neural Inhibition / genetics
-
Neurons / metabolism
-
Phosphatidylinositol 3-Kinases / drug effects
-
Presynaptic Terminals / drug effects*
-
Presynaptic Terminals / metabolism
-
Pro-Opiomelanocortin / metabolism
-
Receptor, Melanocortin, Type 3 / drug effects
-
Receptor, Melanocortin, Type 4 / drug effects
-
Receptors, Leptin / genetics
-
Receptors, Metabotropic Glutamate
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Synapses / drug effects*
-
Synapses / metabolism
-
TRPC Cation Channels / drug effects
-
Type C Phospholipases / drug effects
Substances
-
Blood Glucose
-
Leptin
-
Receptor, Melanocortin, Type 3
-
Receptor, Melanocortin, Type 4
-
Receptors, Leptin
-
Receptors, Metabotropic Glutamate
-
TRPC Cation Channels
-
leptin receptor, mouse
-
Pro-Opiomelanocortin
-
Phosphatidylinositol 3-Kinases
-
Janus Kinase 2
-
AMP-Activated Protein Kinases
-
Type C Phospholipases
-
Glucose