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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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Schematic representation of synaptic inputs to PPG neurons. PPG neurons (yellow) express leptin receptors (Hisadome et al. [19]) and receive direct glutamatergic input both from the tractus solitarius (TS; TTX-insensitive; Hisadome et al. [(19)]) and local glutamatergic neurons (green; TTX-sensitive). Input from adrenergic/noradrenergic neurons (pink) is indirect via α1-adrenergic receptors, activation of which enhances glutamatergic input to PPG neurons. CCK enhances the activity of PPG neurons. Its effect is occluded by either α-adrenergic receptor antagonists or non-NMDA glutamate receptor antagonists. Thus, it acts either on (nor)adrenergic cells or presynaptic from those, as suggested by Baptista et al. (37).
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Figure 6: Schematic representation of synaptic inputs to PPG neurons. PPG neurons (yellow) express leptin receptors (Hisadome et al. [19]) and receive direct glutamatergic input both from the tractus solitarius (TS; TTX-insensitive; Hisadome et al. [(19)]) and local glutamatergic neurons (green; TTX-sensitive). Input from adrenergic/noradrenergic neurons (pink) is indirect via α1-adrenergic receptors, activation of which enhances glutamatergic input to PPG neurons. CCK enhances the activity of PPG neurons. Its effect is occluded by either α-adrenergic receptor antagonists or non-NMDA glutamate receptor antagonists. Thus, it acts either on (nor)adrenergic cells or presynaptic from those, as suggested by Baptista et al. (37).

Mentions: It is well established that CCK activates vagal primary afferents, interacting with CCK receptors in the periphery (22,23,34,35), but potentially also directly within the dorsal vagal complex (27,31,36). It has been shown that neurons of the NTS centralis were stimulated by CCK-8 via an increase in spontaneous glutamatergic but not GABAergic synaptic transmission (37), similar to the observation made here. In contrast with our current observations, however, Baptista et al. (37) found that the effect of CCK persisted in the presence of TTX, suggesting a direct presynaptic effect of CCK. In their study, ∼50% of those cells that responded to CCK were tyrosine hydroxylase immunoreactive and thus catecholaminergic. Catecholaminergic NTS neurons tend to be second order neurons (38), but a follow-up study by Baptista et al. (27) showed that the CCK response persisted in vagally deafferented rats, thus suggesting that CCK does not necessarily act on vagal terminals within the NTS. Our present study also indicates that although PPG neurons are mainly second order neurons (19), CCK-8 has no effect on the vagal afferents impinging directly onto these cells, but likely involves the activation of catecholaminergic cells, which modulate the release of glutamate onto the PPG neurons (Fig. 6).


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)

Schematic representation of synaptic inputs to PPG neurons. PPG neurons (yellow) express leptin receptors (Hisadome et al. [19]) and receive direct glutamatergic input both from the tractus solitarius (TS; TTX-insensitive; Hisadome et al. [(19)]) and local glutamatergic neurons (green; TTX-sensitive). Input from adrenergic/noradrenergic neurons (pink) is indirect via α1-adrenergic receptors, activation of which enhances glutamatergic input to PPG neurons. CCK enhances the activity of PPG neurons. Its effect is occluded by either α-adrenergic receptor antagonists or non-NMDA glutamate receptor antagonists. Thus, it acts either on (nor)adrenergic cells or presynaptic from those, as suggested by Baptista et al. (37).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Schematic representation of synaptic inputs to PPG neurons. PPG neurons (yellow) express leptin receptors (Hisadome et al. [19]) and receive direct glutamatergic input both from the tractus solitarius (TS; TTX-insensitive; Hisadome et al. [(19)]) and local glutamatergic neurons (green; TTX-sensitive). Input from adrenergic/noradrenergic neurons (pink) is indirect via α1-adrenergic receptors, activation of which enhances glutamatergic input to PPG neurons. CCK enhances the activity of PPG neurons. Its effect is occluded by either α-adrenergic receptor antagonists or non-NMDA glutamate receptor antagonists. Thus, it acts either on (nor)adrenergic cells or presynaptic from those, as suggested by Baptista et al. (37).
Mentions: It is well established that CCK activates vagal primary afferents, interacting with CCK receptors in the periphery (22,23,34,35), but potentially also directly within the dorsal vagal complex (27,31,36). It has been shown that neurons of the NTS centralis were stimulated by CCK-8 via an increase in spontaneous glutamatergic but not GABAergic synaptic transmission (37), similar to the observation made here. In contrast with our current observations, however, Baptista et al. (37) found that the effect of CCK persisted in the presence of TTX, suggesting a direct presynaptic effect of CCK. In their study, ∼50% of those cells that responded to CCK were tyrosine hydroxylase immunoreactive and thus catecholaminergic. Catecholaminergic NTS neurons tend to be second order neurons (38), but a follow-up study by Baptista et al. (27) showed that the CCK response persisted in vagally deafferented rats, thus suggesting that CCK does not necessarily act on vagal terminals within the NTS. Our present study also indicates that although PPG neurons are mainly second order neurons (19), CCK-8 has no effect on the vagal afferents impinging directly onto these cells, but likely involves the activation of catecholaminergic cells, which modulate the release of glutamate onto the PPG neurons (Fig. 6).

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