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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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CCK stimulation of spontaneous EPSCs is sensitive to yohimbine. A: Overlay of 15 consecutive 500 ms traces from a recording like that shown in Fig. 2B in the presence of CCK (top) and CCK after preincubation with yohimbine (second from top). CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. This effect could be blocked by 10 μmol/L yohimbine. Bottom two traces show overlays from a recording where CCK was first applied alone (top trace) and then in the presence of the β-adrenoreceptor antagonist ICI118,551 hydrochloride (10 μmol/L; bottom trace). The CCK effect was not reduced by the β-adrenoreceptor antagonist. B: Mean normalized effects of CCK in the presence or absence of various drugs on sEPSC frequency from recordings as depicted in A. 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 CCK is blocked by yohimbine (10 μmol/L) but not ICI118,551. *P < 0.05 compared with control; ##P < 0.01 compared with CCK. Numbers of cells tested are given above the bars.
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Figure 5: CCK stimulation of spontaneous EPSCs is sensitive to yohimbine. A: Overlay of 15 consecutive 500 ms traces from a recording like that shown in Fig. 2B in the presence of CCK (top) and CCK after preincubation with yohimbine (second from top). CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. This effect could be blocked by 10 μmol/L yohimbine. Bottom two traces show overlays from a recording where CCK was first applied alone (top trace) and then in the presence of the β-adrenoreceptor antagonist ICI118,551 hydrochloride (10 μmol/L; bottom trace). The CCK effect was not reduced by the β-adrenoreceptor antagonist. B: Mean normalized effects of CCK in the presence or absence of various drugs on sEPSC frequency from recordings as depicted in A. 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 CCK is blocked by yohimbine (10 μmol/L) but not ICI118,551. *P < 0.05 compared with control; ##P < 0.01 compared with CCK. Numbers of cells tested are given above the bars.

Mentions: Yohimbine (10 μmol/L), an α-receptor antagonist, had no significant effect on sEPSC frequency by itself (n = 5) but prevented the stimulatory effect of epinephrine on EPSC frequency (Fig. 4; n = 5). Similarly, yohimbine prevented the increase in EPSC frequency triggered by 100 nmol/L CCK-8s (n = 4; Fig. 5). By contrast, the β-adrenoreceptor antagonist ICI-118,551 (10 μmol/L) failed to reduce the stimulatory effect of CCK-8s on EPSC frequency (n = 5; Fig. 5). These results suggest that CCK acts on PPG neurons via modulation of adrenergic inputs.


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)

CCK stimulation of spontaneous EPSCs is sensitive to yohimbine. A: Overlay of 15 consecutive 500 ms traces from a recording like that shown in Fig. 2B in the presence of CCK (top) and CCK after preincubation with yohimbine (second from top). CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. This effect could be blocked by 10 μmol/L yohimbine. Bottom two traces show overlays from a recording where CCK was first applied alone (top trace) and then in the presence of the β-adrenoreceptor antagonist ICI118,551 hydrochloride (10 μmol/L; bottom trace). The CCK effect was not reduced by the β-adrenoreceptor antagonist. B: Mean normalized effects of CCK in the presence or absence of various drugs on sEPSC frequency from recordings as depicted in A. 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 CCK is blocked by yohimbine (10 μmol/L) but not ICI118,551. *P < 0.05 compared with control; ##P < 0.01 compared with CCK. Numbers of cells tested are given above the bars.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198097&req=5

Figure 5: CCK stimulation of spontaneous EPSCs is sensitive to yohimbine. A: Overlay of 15 consecutive 500 ms traces from a recording like that shown in Fig. 2B in the presence of CCK (top) and CCK after preincubation with yohimbine (second from top). CCK-8s, bath-applied at 100 nmol/L, led to an increase in sEPSC frequency. This effect could be blocked by 10 μmol/L yohimbine. Bottom two traces show overlays from a recording where CCK was first applied alone (top trace) and then in the presence of the β-adrenoreceptor antagonist ICI118,551 hydrochloride (10 μmol/L; bottom trace). The CCK effect was not reduced by the β-adrenoreceptor antagonist. B: Mean normalized effects of CCK in the presence or absence of various drugs on sEPSC frequency from recordings as depicted in A. 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 CCK is blocked by yohimbine (10 μmol/L) but not ICI118,551. *P < 0.05 compared with control; ##P < 0.01 compared with CCK. Numbers of cells tested are given above the bars.
Mentions: Yohimbine (10 μmol/L), an α-receptor antagonist, had no significant effect on sEPSC frequency by itself (n = 5) but prevented the stimulatory effect of epinephrine on EPSC frequency (Fig. 4; n = 5). Similarly, yohimbine prevented the increase in EPSC frequency triggered by 100 nmol/L CCK-8s (n = 4; Fig. 5). By contrast, the β-adrenoreceptor antagonist ICI-118,551 (10 μmol/L) failed to reduce the stimulatory effect of CCK-8s on EPSC frequency (n = 5; Fig. 5). These results suggest that CCK acts on PPG neurons via modulation of adrenergic inputs.

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