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CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs.

Hisadome K, Reimann F, Gribble FM, Trapp S - Diabetes (2011)

Bottom Line: Inhibition of adrenergic signaling abolished the excitatory action of CCK.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.

ABSTRACT

Objective: Glucagon-like peptide 1 (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, cholecystokinin (CCK), has also been linked to activation of brain stem neurons, suggesting that it might act partially via centrally projecting neurons from the nucleus tractus solitarius (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.

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Related in: MedlinePlus

Epinephrine acts on α1-adrenoreceptors and increases the frequency of spontaneous glutamatergic EPSCs. A: Voltage-clamp recording from a PPG neuron at a holding potential (VH) of −70 mV demonstrating the effects of epinephrine on sEPSCs. B: Overlay of 15 consecutive 500 ms traces from the recording shown in A under control conditions (top) and in the presence of epinephrine (bottom). C: Overlay of 15 consecutive 500 ms traces under control conditions and in the presence of phenylephrine or clonidine, respectively, as indicated above each overlay. Phenylephrine, but not clonidine, led to an increase in sEPSC frequency. D: Mean normalized effects of epinephrine and selective α1- (phenylephrine) and α2- (clonidine, dexmedetomidine) adrenoreceptor agonists on sEPSC frequency. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The effect of epinephrine is blocked by the glutamate receptor antagonist kynurenic acid (Kyn) and by the α-adrenergic receptor antagonist yohimbine. Yohimbine also blocked the effect of phenylephrine. Kyn itself blocked the majority of sEPSCs. *P < 0.05, **P < 0.01, compared with control. Numbers of cells tested are given above the bars.
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Figure 4: Epinephrine acts on α1-adrenoreceptors and increases the frequency of spontaneous glutamatergic EPSCs. A: Voltage-clamp recording from a PPG neuron at a holding potential (VH) of −70 mV demonstrating the effects of epinephrine on sEPSCs. B: Overlay of 15 consecutive 500 ms traces from the recording shown in A under control conditions (top) and in the presence of epinephrine (bottom). C: Overlay of 15 consecutive 500 ms traces under control conditions and in the presence of phenylephrine or clonidine, respectively, as indicated above each overlay. Phenylephrine, but not clonidine, led to an increase in sEPSC frequency. D: Mean normalized effects of epinephrine and selective α1- (phenylephrine) and α2- (clonidine, dexmedetomidine) adrenoreceptor agonists on sEPSC frequency. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The effect of epinephrine is blocked by the glutamate receptor antagonist kynurenic acid (Kyn) and by the α-adrenergic receptor antagonist yohimbine. Yohimbine also blocked the effect of phenylephrine. Kyn itself blocked the majority of sEPSCs. *P < 0.05, **P < 0.01, compared with control. Numbers of cells tested are given above the bars.

Mentions: The ionotropic glutamate receptor antagonist kynurenic acid (1 mmol/L) reduced the frequency of synaptic events by 93 ± 4% (n = 5; Fig. 4), whereas epinephrine (10 μmol/L; n = 12) significantly increased the frequency of EPSCs (Fig. 4). However, in the presence of 1 mmol/L kynurenic acid the effect of epinephrine was occluded (n = 4), thus verifying that epinephrine acted by modulating the glutamatergic input onto the PPG cells (Fig. 4). The α2-adrenoceptor agonists clonidine (10 μmol/L) and dexmedetomidine (1 μmol/L) had no significant effect on EPSC frequency, whereas the α1-receptor agonist phenylephrine (50 μmol/L) significantly increased EPSC frequency (Fig. 4).


CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs.

Hisadome K, Reimann F, Gribble FM, Trapp S - Diabetes (2011)

Epinephrine acts on α1-adrenoreceptors and increases the frequency of spontaneous glutamatergic EPSCs. A: Voltage-clamp recording from a PPG neuron at a holding potential (VH) of −70 mV demonstrating the effects of epinephrine on sEPSCs. B: Overlay of 15 consecutive 500 ms traces from the recording shown in A under control conditions (top) and in the presence of epinephrine (bottom). C: Overlay of 15 consecutive 500 ms traces under control conditions and in the presence of phenylephrine or clonidine, respectively, as indicated above each overlay. Phenylephrine, but not clonidine, led to an increase in sEPSC frequency. D: Mean normalized effects of epinephrine and selective α1- (phenylephrine) and α2- (clonidine, dexmedetomidine) adrenoreceptor agonists on sEPSC frequency. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The effect of epinephrine is blocked by the glutamate receptor antagonist kynurenic acid (Kyn) and by the α-adrenergic receptor antagonist yohimbine. Yohimbine also blocked the effect of phenylephrine. Kyn itself blocked the majority of sEPSCs. *P < 0.05, **P < 0.01, compared with control. Numbers of cells tested are given above the bars.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 4: Epinephrine acts on α1-adrenoreceptors and increases the frequency of spontaneous glutamatergic EPSCs. A: Voltage-clamp recording from a PPG neuron at a holding potential (VH) of −70 mV demonstrating the effects of epinephrine on sEPSCs. B: Overlay of 15 consecutive 500 ms traces from the recording shown in A under control conditions (top) and in the presence of epinephrine (bottom). C: Overlay of 15 consecutive 500 ms traces under control conditions and in the presence of phenylephrine or clonidine, respectively, as indicated above each overlay. Phenylephrine, but not clonidine, led to an increase in sEPSC frequency. D: Mean normalized effects of epinephrine and selective α1- (phenylephrine) and α2- (clonidine, dexmedetomidine) adrenoreceptor agonists on sEPSC frequency. The mean sEPSC frequency in presence of the drug (freqD) as a fraction of the frequency in the absence of any drug (freqC) is plotted. The effect of epinephrine is blocked by the glutamate receptor antagonist kynurenic acid (Kyn) and by the α-adrenergic receptor antagonist yohimbine. Yohimbine also blocked the effect of phenylephrine. Kyn itself blocked the majority of sEPSCs. *P < 0.05, **P < 0.01, compared with control. Numbers of cells tested are given above the bars.
Mentions: The ionotropic glutamate receptor antagonist kynurenic acid (1 mmol/L) reduced the frequency of synaptic events by 93 ± 4% (n = 5; Fig. 4), whereas epinephrine (10 μmol/L; n = 12) significantly increased the frequency of EPSCs (Fig. 4). However, in the presence of 1 mmol/L kynurenic acid the effect of epinephrine was occluded (n = 4), thus verifying that epinephrine acted by modulating the glutamatergic input onto the PPG cells (Fig. 4). The α2-adrenoceptor agonists clonidine (10 μmol/L) and dexmedetomidine (1 μmol/L) had no significant effect on EPSC frequency, whereas the α1-receptor agonist phenylephrine (50 μmol/L) significantly increased EPSC frequency (Fig. 4).

Bottom Line: Inhibition of adrenergic signaling abolished the excitatory action of CCK.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.

ABSTRACT

Objective: Glucagon-like peptide 1 (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, cholecystokinin (CCK), has also been linked to activation of brain stem neurons, suggesting that it might act partially via centrally projecting neurons from the nucleus tractus solitarius (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.

Show MeSH
Related in: MedlinePlus