Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

Nov 5, 2020Neuroendocrinology

Glucagon-Like Peptide-1 Controls Appetite-Regulating Neurons in the Hypothalamus Both Directly and Through Incoming Signals

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Abstract

GLP-1 signaling is associated with increased neuronal activity in proopiomelanocortin (POMC) neurons.

GLP-1 receptors are found on the cell membrane of POMC neurons and on axon terminals that make synapses with these cells.
The GLP-1 analog exendin 4 (Ex4) significantly raises the firing rate of POMC neurons and causes depolarization.
Ex4 enhances the frequency of miniature excitatory postsynaptic currents (EPSCs) and increases the amplitude of evoked EPSCs in some POMC neurons.
Increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and their amplitudes in a subset of neurons were also observed after Ex4 treatment.
The effects of Ex4 on POMC neurons suggest that GLP-1 signaling may enhance presynaptic input by acting on localized GLP-1 receptors.

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Glucagon-like peptide-1 (GLP-1) exerts its anorexigenic effect at least partly via the proopiomelanocortin (POMC) neurons of the arcuate (ARC) nucleus. These neurons are known to express GLP-1 receptor (GLP-1R). The aim of the study was to determine whether in addition to its direct effect, GLP-1 also modulates how neuronal inputs can regulate the POMC neurons by acting on presynaptic terminals, ultrastructural and electrophysiological studies were performed on tissues of adult male mice. GLP-1R-immunoreactivity was associated with the cell membrane of POMC neurons and with axon terminals forming synapses on these cells. The GLP-1 analog exendin 4 (Ex4) markedly increased the firing rate of all examined POMC neurons and depolarized these cells. These effects of Ex4 were prevented by intracellular administration of the G-protein blocker guanosine 5'-[β-thio]diphosphate trilithium salt (GDP-β-S). Ex4 also influenced the miniature postsynaptic currents (mPSCs) and evoked PSCs of POMC neurons. Ex4 increased the frequency of miniature excitatory PSCs (EPSCs) and the amplitude of the evoked EPSCs in half of the POMC neurons. Ex4 increased the frequency of miniature inhibitory PSCs (IPSCs) and the amplitudes of the evoked IPSCs in one-third of neurons. These effects of Ex4 were not influenced by intracellular GDP-β-S, indicating that GLP-1 signaling directly stimulates a population of axon terminals innervating the POMC neurons. The different Ex4 responsiveness of their mPSCs indicates the heterogeneity of the POMC neurons of the ARC. In summary, our data demonstrate that in addition to its direct excitatory effect on the POMC neurons, GLP-1 signaling also facilitates the presynaptic input of these cells by acting on presynaptically localized GLP-1R.

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Glucagon-Like Peptide-1 Regulates the Proopiomelanocortin Neurons of the Arcuate Nucleus both Directly and Indirectly via Presynaptic Action

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