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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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Epinephrine stimulation of firing frequency of PPG neurons is occluded by DNQX. A: Current-clamp recording showing the effect of bath application of 100 μmol/L norepinephrine on firing frequency of PPG neuron. B: Bath application of 10 μmol/L epinephrine leads to an increase in spontaneous action potential firing frequency of PPG neurons. This effect of epinephrine is prevented by the non-NMDA glutamate receptor antagonist DNQX (10 μmol/L). Top: instantaneous firing frequency; bottom: segments of the original current-clamp recording at time points i, ii, iii, and iv, indicated by arrows. C: Mean data for the change in firing frequency (FR) during experiments as shown in A. Epinephrine (10 μmol/L) and 100 μmol/L norepinephrine, but not 100 nmol/L Melanotan II (MT-II), 10 μmol/L norepinephrine, or 10 μmol/L dopamine significantly increased firing rate. The effect of 10 μmol/L epinephrine is occluded by 10 μmol/L DNQX. Number of recordings for each condition is given above the bars. *P < 0.05, **P < 0.01, compared with control; ##P < 0.01 compared with epinephrine.
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Figure 3: Epinephrine stimulation of firing frequency of PPG neurons is occluded by DNQX. A: Current-clamp recording showing the effect of bath application of 100 μmol/L norepinephrine on firing frequency of PPG neuron. B: Bath application of 10 μmol/L epinephrine leads to an increase in spontaneous action potential firing frequency of PPG neurons. This effect of epinephrine is prevented by the non-NMDA glutamate receptor antagonist DNQX (10 μmol/L). Top: instantaneous firing frequency; bottom: segments of the original current-clamp recording at time points i, ii, iii, and iv, indicated by arrows. C: Mean data for the change in firing frequency (FR) during experiments as shown in A. Epinephrine (10 μmol/L) and 100 μmol/L norepinephrine, but not 100 nmol/L Melanotan II (MT-II), 10 μmol/L norepinephrine, or 10 μmol/L dopamine significantly increased firing rate. The effect of 10 μmol/L epinephrine is occluded by 10 μmol/L DNQX. Number of recordings for each condition is given above the bars. *P < 0.05, **P < 0.01, compared with control; ##P < 0.01 compared with epinephrine.

Mentions: POMC neurons within the NTS were shown previously to be activated by peripherally administered CCK, as determined by cFOS staining (25,32). Furthermore, CCK administration failed to suppress food intake in the hyperphagic melanocortin receptor 4 (MC-4) knock-out mouse model (25). Consequently, we tested whether PPG neurons are electrically stimulated by MC-4 receptor activation. Bath application of the melanocortin receptor agonist MT-II (100 nmol/L) had no significant effect on firing rate (1.5 ± 0.7 Hz vs. 1.7 ± 0.8 Hz; Fig. 3), membrane potential (−52 ± 1 mV vs. −52 ± 2 mV), or input resistance of PPG neurons (n = 7), thus making it unlikely that the observed effects of CCK on PPG cells are mediated via NTS POMC neurons.


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 stimulation of firing frequency of PPG neurons is occluded by DNQX. A: Current-clamp recording showing the effect of bath application of 100 μmol/L norepinephrine on firing frequency of PPG neuron. B: Bath application of 10 μmol/L epinephrine leads to an increase in spontaneous action potential firing frequency of PPG neurons. This effect of epinephrine is prevented by the non-NMDA glutamate receptor antagonist DNQX (10 μmol/L). Top: instantaneous firing frequency; bottom: segments of the original current-clamp recording at time points i, ii, iii, and iv, indicated by arrows. C: Mean data for the change in firing frequency (FR) during experiments as shown in A. Epinephrine (10 μmol/L) and 100 μmol/L norepinephrine, but not 100 nmol/L Melanotan II (MT-II), 10 μmol/L norepinephrine, or 10 μmol/L dopamine significantly increased firing rate. The effect of 10 μmol/L epinephrine is occluded by 10 μmol/L DNQX. Number of recordings for each condition is given above the bars. *P < 0.05, **P < 0.01, compared with control; ##P < 0.01 compared with epinephrine.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198097&req=5

Figure 3: Epinephrine stimulation of firing frequency of PPG neurons is occluded by DNQX. A: Current-clamp recording showing the effect of bath application of 100 μmol/L norepinephrine on firing frequency of PPG neuron. B: Bath application of 10 μmol/L epinephrine leads to an increase in spontaneous action potential firing frequency of PPG neurons. This effect of epinephrine is prevented by the non-NMDA glutamate receptor antagonist DNQX (10 μmol/L). Top: instantaneous firing frequency; bottom: segments of the original current-clamp recording at time points i, ii, iii, and iv, indicated by arrows. C: Mean data for the change in firing frequency (FR) during experiments as shown in A. Epinephrine (10 μmol/L) and 100 μmol/L norepinephrine, but not 100 nmol/L Melanotan II (MT-II), 10 μmol/L norepinephrine, or 10 μmol/L dopamine significantly increased firing rate. The effect of 10 μmol/L epinephrine is occluded by 10 μmol/L DNQX. Number of recordings for each condition is given above the bars. *P < 0.05, **P < 0.01, compared with control; ##P < 0.01 compared with epinephrine.
Mentions: POMC neurons within the NTS were shown previously to be activated by peripherally administered CCK, as determined by cFOS staining (25,32). Furthermore, CCK administration failed to suppress food intake in the hyperphagic melanocortin receptor 4 (MC-4) knock-out mouse model (25). Consequently, we tested whether PPG neurons are electrically stimulated by MC-4 receptor activation. Bath application of the melanocortin receptor agonist MT-II (100 nmol/L) had no significant effect on firing rate (1.5 ± 0.7 Hz vs. 1.7 ± 0.8 Hz; Fig. 3), membrane potential (−52 ± 1 mV vs. −52 ± 2 mV), or input resistance of PPG neurons (n = 7), thus making it unlikely that the observed effects of CCK on PPG cells are mediated via NTS POMC neurons.

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