CCK Stimulation of GLP-1 Neurons Involves α1-Adrenoceptor–Mediated Increase in Glutamatergic Synaptic Inputs

Sep 3, 2011Diabetes

CCK activates GLP-1 neurons by increasing excitatory signals through α1-adrenoceptors

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Abstract

activates -PPG neurons in response to signals related to food intake.

PPG neurons in the NTS are excited by CCK and epinephrine.
Melanotan II does not activate PPG neurons.
CCK and epinephrine increase glutamatergic transmission to PPG neurons.
Activation of α(1)-adrenergic receptors is involved in the excitatory effects of CCK.
Inhibition of adrenergic signaling prevents CCK from exciting PPG neurons.

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OBJECTIVE: (GLP-1) is involved in the central regulation of food intake. It is produced within the brain by preproglucagon (PPG) neurons, which are located primarily within the brain stem. These neurons project widely throughout the brain, including to the appetite centers in the hypothalamus, and are believed to convey signals related to satiety. Previous work demonstrated that they are directly activated by leptin and electrical activity of the afferent vagus. Another satiety hormone, (CCK), has also been linked to activation of brain stem neurons, suggesting that it might act partially via centrally projecting neurons from the (NTS). The aim of this study was to investigate the neuronal circuitry linking CCK to the population of NTS-PPG neurons.

RESEARCH DESIGN AND METHODS: Transgenic mice expressing yellow fluorescent protein (Venus) under the control of the PPG promoter were used to identify PPG neurons in vitro and to record their electrical and pharmacological profile.

RESULTS: PPG neurons in the NTS were excited by CCK and epinephrine, but not by the melanocortin receptor agonist melanotan II. Both CCK and epinephrine acted to increase glutamatergic transmission to the PPG neurons, and this involved activation of α(1)-adrenergic receptors. Inhibition of adrenergic signaling abolished the excitatory action of CCK.

CONCLUSIONS: CCK activates NTS-PPG cells by a circuit involving adrenergic and glutamatergic neurons. NTS-PPG neurons integrate a variety of peripheral signals that indicate both long-term energy balance and short-term nutritional and digestional status to produce an output signal to feeding and autonomic circuits.

Key numbers

104 ± 34%

Increase in Action Potential Frequency

Frequency increase in action potentials after application in PPG neurons.

7 of 15

Percentage of Neurons Responding to

Number of PPG neurons showing increased firing rate after application.

91 ± 5%

Inhibition of Spontaneous EPSCs by DNQX

Percentage inhibition of spontaneous excitatory postsynaptic currents by the antagonist.

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CCK Stimulation of GLP-1 Neurons Involves α1-Adrenoceptor–Mediated Increase in Glutamatergic Synaptic Inputs

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