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Stefan Trapp - One of the best experts on this subject based on the ideXlab platform.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. While the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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A unique olfactory bulb microcircuit driven by neurons expressing the precursor to glucagon-like peptide 1
Scientific Reports, 2019Co-Authors: Nicolas Thiebaud, Fiona Gribble, Frank Reimann, Stefan Trapp, Debra Ann FadoolAbstract:The presence of large numbers of local interneurons in the olfactory bulb has demonstrated an extensive local signaling process, yet the identification and purpose of olfactory microcircuits is poorly explored. Because the discrimination of odors in a complex environment is highly dependent on the tuning of information by local interneurons, we studied for the first time the role of Preproglucagon (PPG) neurons in the granule cell layer of the olfactory bulb. Combining electrophysiological recordings and confocal microscopy, we discovered that the PPG neurons are a population of cells expressing the precursor of glucagon-like peptide 1 and are glutamatergic; able to modulate the firing pattern of the mitral cells (M/TCs). Optogenetic activation of PPG neurons resulted in a mixed excitation and inhibition that created a multiphasic response shaping the M/TCs firing pattern. This suggests that PPG neurons could drive neuromodulation of the olfactory output and change the synaptic map regulating olfactory coding.
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Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain glp 1 mediate stress induced hypophagia and limit unusually large intakes of food
Diabetes, 2019Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, D J L Williams, Fiona M Gribble, Stefan TrappAbstract:Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
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serotonergic modulation of the activity of glp 1 producing neurons in the nucleus of the solitary tract in mouse
Molecular metabolism, 2017Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Ida J Llewellynsmith, Stefan TrappAbstract:Objective Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by Preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT.
Frank Reimann - One of the best experts on this subject based on the ideXlab platform.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. While the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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synaptic inputs to the mouse dorsal vagal complex and its resident Preproglucagon neurons
The Journal of Neuroscience, 2019Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Lisa E Pomeranz, Kevin T Beier, Linda RinamanAbstract:Stress responses are coordinated by widespread neural circuits. Homeostatic and psychogenic stressors activate Preproglucagon (PPG) neurons in the caudal nucleus of the solitary tract (cNTS) that produce glucagon-like peptide-1; published work in rodents indicates that these neurons play a crucial role in stress responses. While the axonal targets of PPG neurons are well established, their afferent inputs are unknown. Here we use retrograde tracing with cholera toxin subunit b to show that the cNTS in male and female mice receives axonal inputs similar to those reported in rats. Monosynaptic and polysynaptic inputs specific to cNTS PPG neurons were revealed using Cre-conditional pseudorabies and rabies viruses. The most prominent sources of PPG monosynaptic input include the lateral (LH) and paraventricular (PVN) nuclei of the hypothalamus, parasubthalamic nucleus, lateral division of the central amygdala, and Barrington's nucleus (Bar). Additionally, PPG neurons receive monosynaptic vagal sensory input from the nodose ganglia and spinal sensory input from the dorsal horn. Sources of polysynaptic input to cNTS PPG neurons include the hippocampal formation, paraventricular thalamus, and prefrontal cortex. Finally, cNTS-projecting neurons within PVN, LH, and Bar express the activation marker cFOS in mice after restraint stress, identifying them as potential sources of neurogenic stress-induced recruitment of PPG neurons. In summary, cNTS PPG neurons in mice receive widespread monosynaptic and polysynaptic input from brain regions implicated in coordinating behavioral and physiological stress responses, as well as from vagal and spinal sensory neurons. Thus, PPG neurons are optimally positioned to integrate signals of homeostatic and psychogenic stress.SIGNIFICANCE STATEMENT Recent research has indicated a crucial role for glucagon-like peptide-1-producing Preproglucagon (PPG) neurons in regulating both appetite and behavioral and autonomic responses to acute stress. Intriguingly, the central glucagon-like peptide-1 system defined in rodents is conserved in humans, highlighting the translational importance of understanding its anatomical organization. Findings reported here indicate that PPG neurons receive significant monosynaptic and polysynaptic input from brain regions implicated in autonomic and behavioral responses to stress, as well as direct input from vagal and spinal sensory neurons. Improved understanding of the neural pathways underlying the recruitment of PPG neurons may facilitate the development of novel therapies for the treatment of stress-related disorders.
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A unique olfactory bulb microcircuit driven by neurons expressing the precursor to glucagon-like peptide 1
Scientific Reports, 2019Co-Authors: Nicolas Thiebaud, Fiona Gribble, Frank Reimann, Stefan Trapp, Debra Ann FadoolAbstract:The presence of large numbers of local interneurons in the olfactory bulb has demonstrated an extensive local signaling process, yet the identification and purpose of olfactory microcircuits is poorly explored. Because the discrimination of odors in a complex environment is highly dependent on the tuning of information by local interneurons, we studied for the first time the role of Preproglucagon (PPG) neurons in the granule cell layer of the olfactory bulb. Combining electrophysiological recordings and confocal microscopy, we discovered that the PPG neurons are a population of cells expressing the precursor of glucagon-like peptide 1 and are glutamatergic; able to modulate the firing pattern of the mitral cells (M/TCs). Optogenetic activation of PPG neurons resulted in a mixed excitation and inhibition that created a multiphasic response shaping the M/TCs firing pattern. This suggests that PPG neurons could drive neuromodulation of the olfactory output and change the synaptic map regulating olfactory coding.
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Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain glp 1 mediate stress induced hypophagia and limit unusually large intakes of food
Diabetes, 2019Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, D J L Williams, Fiona M Gribble, Stefan TrappAbstract:Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
Fiona M Gribble - One of the best experts on this subject based on the ideXlab platform.
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synaptic inputs to the mouse dorsal vagal complex and its resident Preproglucagon neurons
The Journal of Neuroscience, 2019Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Lisa E Pomeranz, Kevin T Beier, Linda RinamanAbstract:Stress responses are coordinated by widespread neural circuits. Homeostatic and psychogenic stressors activate Preproglucagon (PPG) neurons in the caudal nucleus of the solitary tract (cNTS) that produce glucagon-like peptide-1; published work in rodents indicates that these neurons play a crucial role in stress responses. While the axonal targets of PPG neurons are well established, their afferent inputs are unknown. Here we use retrograde tracing with cholera toxin subunit b to show that the cNTS in male and female mice receives axonal inputs similar to those reported in rats. Monosynaptic and polysynaptic inputs specific to cNTS PPG neurons were revealed using Cre-conditional pseudorabies and rabies viruses. The most prominent sources of PPG monosynaptic input include the lateral (LH) and paraventricular (PVN) nuclei of the hypothalamus, parasubthalamic nucleus, lateral division of the central amygdala, and Barrington's nucleus (Bar). Additionally, PPG neurons receive monosynaptic vagal sensory input from the nodose ganglia and spinal sensory input from the dorsal horn. Sources of polysynaptic input to cNTS PPG neurons include the hippocampal formation, paraventricular thalamus, and prefrontal cortex. Finally, cNTS-projecting neurons within PVN, LH, and Bar express the activation marker cFOS in mice after restraint stress, identifying them as potential sources of neurogenic stress-induced recruitment of PPG neurons. In summary, cNTS PPG neurons in mice receive widespread monosynaptic and polysynaptic input from brain regions implicated in coordinating behavioral and physiological stress responses, as well as from vagal and spinal sensory neurons. Thus, PPG neurons are optimally positioned to integrate signals of homeostatic and psychogenic stress.SIGNIFICANCE STATEMENT Recent research has indicated a crucial role for glucagon-like peptide-1-producing Preproglucagon (PPG) neurons in regulating both appetite and behavioral and autonomic responses to acute stress. Intriguingly, the central glucagon-like peptide-1 system defined in rodents is conserved in humans, highlighting the translational importance of understanding its anatomical organization. Findings reported here indicate that PPG neurons receive significant monosynaptic and polysynaptic input from brain regions implicated in autonomic and behavioral responses to stress, as well as direct input from vagal and spinal sensory neurons. Improved understanding of the neural pathways underlying the recruitment of PPG neurons may facilitate the development of novel therapies for the treatment of stress-related disorders.
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Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain glp 1 mediate stress induced hypophagia and limit unusually large intakes of food
Diabetes, 2019Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, D J L Williams, Fiona M Gribble, Stefan TrappAbstract:Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
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serotonergic modulation of the activity of glp 1 producing neurons in the nucleus of the solitary tract in mouse
Molecular metabolism, 2017Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Ida J Llewellynsmith, Stefan TrappAbstract:Objective Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by Preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT.
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Preproglucagon neurons in the hindbrain have il 6 receptor α and show ca2 influx in response to il 6
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2016Co-Authors: Fredrik Anesten, Frank Reimann, Stefan Trapp, Marie K Holt, Fiona M Gribble, Erik Schele, Vilborg Palsdottir, Cecilia Safari, Karolina P Skibicka, Johnolov JanssonAbstract:Neuronal circuits in the hypothalamus and hindbrain are of importance for control of food intake, energy expenditure, and fat mass. We have recently shown that treatment with exendin-4 (Ex-4), an analog of the proglucagon-derived molecule glucagon-like peptide 1 (GLP-1), markedly increases mRNA expression of the cytokine interleukin-6 (IL-6) in the hypothalamus and hindbrain and that this increase partly mediates the suppression of food intake and body weight by Ex-4. Endogenous GLP-1 in the central nervous system (CNS) is produced by Preproglucagon (PPG) neurons of the nucleus of the solitary tract (NTS) in the hindbrain. These neurons project to various parts of the brain, including the hypothalamus. Outside the brain, IL-6 stimulates GLP-1 secretion from the gut and pancreas. In this study, we aim to investigate whether IL-6 can affect GLP-1-producing PPG neurons in the nucleus of the solitary tract (NTS) in mouse hindbrain via the ligand binding part of the IL-6 receptor, IL-6 receptor-α (IL-6Rα). Using immunohistochemistry, we found that IL-6Rα was localized on PPG neurons of the NTS. Recordings of these neurons in GCaMP3/GLP-1 reporter mice showed that IL-6 enhances cytosolic Ca2+ concentration in neurons capable of expressing PPG. We also show that the Ca2+ increase originates from the extracellular space. Furthermore, we found that IL-6Rα was localized on cells in the caudal hindbrain expressing immunoreactive NeuN (a neuronal marker) or CNP:ase (an oligodendrocyte marker). In summary, IL-6Rα is present on PPG neurons in the NTS, and IL-6 can stimulate these cells by increasing influx of Ca2+ to the cytosol from the extracellular space.
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the incretin hormone glucagon like peptide 1 increases mitral cell excitability by decreasing conductance of a voltage dependent potassium channel
The Journal of Physiology, 2016Co-Authors: Nicolas Thiebaud, Frank Reimann, Stefan Trapp, Fiona M Gribble, Ida J Llewellynsmith, Debra Ann FadoolAbstract:KEY POINTS: The gut hormone called glucagon-like peptide 1 (GLP-1) is a strong moderator of energy homeostasis and communication between the peripheral organs and the brain. GLP-1 signalling occurs in the brain; using a newly developed genetic reporter line of mice, we have discovered GLP-synthesizing cells in the olfactory bulb. GLP-1 increases the firing frequency of neurons (mitral cells) that encode olfactory information by decreasing activity of voltage-dependent K channels (Kv1.3). Modifying GLP-1 levels, either therapeutically or following the ingestion of food, could alter the excitability of neurons in the olfactory bulb in a nutrition or energy state-dependent manner to influence olfactory detection or metabolic sensing. The results of the present study uncover a new function for an olfactory bulb neuron (deep short axon cells, Cajal cells) that could be capable of modifying mitral cell activity through the release of GLP-1. This might be of relevance for the action of GLP-1 mimetics now widely used in the treatment of diabetes. ABSTRACT: The olfactory system is intricately linked with the endocrine system where it may serve as a detector of the internal metabolic state or energy homeostasis in addition to its classical function as a sensor of external olfactory information. The recent development of transgenic mGLU-yellow fluorescent protein mice that express a genetic reporter under the control of the Preproglucagon reporter suggested the presence of the gut hormone, glucagon-like peptide (GLP-1), in deep short axon cells (Cajal cells) of the olfactory bulb and its neuromodulatory effect on mitral cell (MC) first-order neurons. A MC target for the peptide was determined using GLP-1 receptor binding assays, immunocytochemistry for the receptor and injection of fluorescence-labelled GLP-1 analogue exendin-4. Using patch clamp recording of olfactory bulb slices in the whole-cell configuration, we report that GLP-1 and its stable analogue exendin-4 increase the action potential firing frequency of MCs by decreasing the interburst interval rather than modifying the action potential shape, train length or interspike interval. GLP-1 decreases Kv1.3 channel contribution to outward currents in voltage clamp recordings as determined by pharmacological blockade of Kv1.3 or utilizing mice with Kv1.3 gene-targeted deletion as a negative control. Because fluctuations in GLP-1 concentrations monitored by the olfactory bulb can modify the firing frequency of MCs, olfactory coding could change depending upon nutritional or physiological state. As a regulator of neuronal activity, GLP-1 or its analogue may comprise a new metabolic factor with a potential therapeutic target in the olfactory bulb (i.e. via intranasal delivery) for controlling an imbalance in energy homeostasis.
Marie K Holt - One of the best experts on this subject based on the ideXlab platform.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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ppg neurons in the nucleus of the solitary tract modulate heart rate but do not mediate glp 1 receptor agonist induced tachycardia in mice
Molecular metabolism, 2020Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, Alexander V Gourine, Nephtali Marina, Stefan TrappAbstract:Abstract Objective Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. While the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate Preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects. Methods We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPGNTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA. Results Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPGNTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPGNTS neurons. PPGNTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPGNTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR. Conclusions These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPGNTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPGNTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.
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synaptic inputs to the mouse dorsal vagal complex and its resident Preproglucagon neurons
The Journal of Neuroscience, 2019Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Lisa E Pomeranz, Kevin T Beier, Linda RinamanAbstract:Stress responses are coordinated by widespread neural circuits. Homeostatic and psychogenic stressors activate Preproglucagon (PPG) neurons in the caudal nucleus of the solitary tract (cNTS) that produce glucagon-like peptide-1; published work in rodents indicates that these neurons play a crucial role in stress responses. While the axonal targets of PPG neurons are well established, their afferent inputs are unknown. Here we use retrograde tracing with cholera toxin subunit b to show that the cNTS in male and female mice receives axonal inputs similar to those reported in rats. Monosynaptic and polysynaptic inputs specific to cNTS PPG neurons were revealed using Cre-conditional pseudorabies and rabies viruses. The most prominent sources of PPG monosynaptic input include the lateral (LH) and paraventricular (PVN) nuclei of the hypothalamus, parasubthalamic nucleus, lateral division of the central amygdala, and Barrington's nucleus (Bar). Additionally, PPG neurons receive monosynaptic vagal sensory input from the nodose ganglia and spinal sensory input from the dorsal horn. Sources of polysynaptic input to cNTS PPG neurons include the hippocampal formation, paraventricular thalamus, and prefrontal cortex. Finally, cNTS-projecting neurons within PVN, LH, and Bar express the activation marker cFOS in mice after restraint stress, identifying them as potential sources of neurogenic stress-induced recruitment of PPG neurons. In summary, cNTS PPG neurons in mice receive widespread monosynaptic and polysynaptic input from brain regions implicated in coordinating behavioral and physiological stress responses, as well as from vagal and spinal sensory neurons. Thus, PPG neurons are optimally positioned to integrate signals of homeostatic and psychogenic stress.SIGNIFICANCE STATEMENT Recent research has indicated a crucial role for glucagon-like peptide-1-producing Preproglucagon (PPG) neurons in regulating both appetite and behavioral and autonomic responses to acute stress. Intriguingly, the central glucagon-like peptide-1 system defined in rodents is conserved in humans, highlighting the translational importance of understanding its anatomical organization. Findings reported here indicate that PPG neurons receive significant monosynaptic and polysynaptic input from brain regions implicated in autonomic and behavioral responses to stress, as well as direct input from vagal and spinal sensory neurons. Improved understanding of the neural pathways underlying the recruitment of PPG neurons may facilitate the development of novel therapies for the treatment of stress-related disorders.
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Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain glp 1 mediate stress induced hypophagia and limit unusually large intakes of food
Diabetes, 2019Co-Authors: Marie K Holt, Frank Reimann, James E Richards, Daniel R Cook, Daniel I Brierley, D J L Williams, Fiona M Gribble, Stefan TrappAbstract:Centrally administered glucagon-like peptide 1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on the ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake after a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding; however, it increased refeeding intake after fast and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation but form part of a secondary satiation/satiety circuit, which is activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.
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serotonergic modulation of the activity of glp 1 producing neurons in the nucleus of the solitary tract in mouse
Molecular metabolism, 2017Co-Authors: Marie K Holt, Frank Reimann, Fiona M Gribble, Ida J Llewellynsmith, Stefan TrappAbstract:Objective Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by Preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT.
Darleen A. Sandoval - One of the best experts on this subject based on the ideXlab platform.
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Preproglucagon products and their respective roles regulating insulin secretion
Endocrinology, 2021Co-Authors: Maigen Bethea, Nadejda Bozadjievakramer, Darleen A. SandovalAbstract:Historically, intracellular function and metabolic adaptation within the α-cell has been understudied, with most of the attention being placed on the insulin-producing β-cells due to their role in the pathophysiology of Type 2 Diabetes Mellitus. However, there is a growing interest in understanding the function of other endocrine cell types within the islet and their paracrine role in regulating insulin secretion. For example, there is greater appreciation for α-cell products and their contributions to overall glucose homeostasis. Several recent studies have addressed a paracrine role for α-cell derived glucagon-like peptide-1 (GLP-1) in regulating glucose homeostasis and responses to metabolic stress. Further, other studies have demonstrated the ability of glucagon to impact insulin secretion by acting through the GLP-1 receptor. These studies challenge the central dogma surrounding α-cell biology describing glucagon's primary role in glucose counter-regulation to one where glucagon is critical in regulating both hyper- and hypoglycemic responses. Herein, this review will update the current understanding of the role of glucagon and α-cell derived GLP-1 placing emphasis on their roles in regulating glucose homeostasis, insulin secretion, and β-cell mass.
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updating the role of α cell Preproglucagon products on glp 1 receptor mediated insulin secretion
Diabetes, 2020Co-Authors: Darleen A. SandovalAbstract:While the field of islet biology has historically focused its attention on understanding β-cell function and the mechanisms by which these cells become dysfunctional with diabetes, there has been a scientific shift toward greater understanding of other endocrine cells of the islet and their paracrine role in regulating the β-cell. In recent years, many questions and new data have come forward regarding the paracrine role of the α-cell and specifically Preproglucagon peptides in regulating insulin secretion. The role of intestinally secreted glucagon-like peptide 1 (GLP-1) in regulation of insulin secretion has been questioned, and a physiological role of pancreatic GLP-1 in regulation of insulin secretion has been proposed. In addition, in the last 2 years, a series of studies demonstrated a physiological role for glucagon, acting via the GLP-1 receptor, in paracrine regulation of insulin secretion. Altogether, this work challenges the textbook physiology of both GLP-1 and glucagon and presents a critical paradigm shift for the field. This article addresses these new findings surrounding α-cell Preproglucagon products, with a particular focus on GLP-1, in the context of their roles in insulin secretion and consequently glucose metabolism.
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Glycemic effect of pancreatic Preproglucagon in mouse sleeve gastrectomy
JCI insight, 2019Co-Authors: Ki-suk Kim, Chelsea R. Hutch, Landon Wood, Irwin J. Magrisso, Randy J. Seeley, Darleen A. SandovalAbstract:Intestinally derived glucagon-like peptide-1 (GLP-1), encoded by the Preproglucagon (Gcg) gene, is believed to function as an incretin. However, our previous work questioned this dogma and demonstrated that pancreatic peptides rather than intestinal Gcg peptides, including GLP-1, are a primary regulator of glucose homeostasis in normal mice. The objective of these experiments was to determine whether changes in nutrition or alteration of gut hormone secretion by bariatric surgery would result in a larger role for intestinal GLP-1 in the regulation of insulin secretion and glucose homeostasis. Multiple transgenic models, including mouse models with intestine- or pancreas tissue-specific Gcg expression and a whole-body Gcg-null mouse model, were generated to study the role of organ-specific GLP-1 production on glucose homeostasis under dietary-induced obesity and after weight loss from bariatric surgery (vertical sleeve gastrectomy; VSG). Our findings indicated that the intestine is a major source of circulating GLP-1 after various nutrient and surgical stimuli. However, even with the 4-fold increase in intestinally derived GLP-1 with VSG, it is pancreatic peptides, not intestinal Gcg peptides, that are necessary for surgery-induced improvements in glucose homeostasis.
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the endogenous Preproglucagon system is not essential for gut growth homeostasis in mice
Molecular metabolism, 2017Co-Authors: Pernille Wismann, Niels Vrang, Daniel J Drucker, Pernille Barkholt, Thomas Secher, Henrik B Hansen, P Jeppesen, Laurie L Baggio, Jacqueline A Koehler, Darleen A. SandovalAbstract:Objective The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice.
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physiology of proglucagon peptides role of glucagon and glp 1 in health and disease
Physical Review, 2015Co-Authors: Darleen A. Sandoval, David A DalessioAbstract:The Preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.