Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist

Baraboi, Elena-Dana; Smith, Pauline; Ferguson, Alastair V.; Richard, Denis

doi:10.1152/ajpregu.00326.2009

Cited by 38 publications

(31 citation statements)

References 69 publications

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“…This actually fits quite nicely with observations and conclusions from other studies that indicate a role for vagal GLP-1Rs in only short-term satiation processes (34,61,62) as well as with findings from a recent publication demonstrating that central GLP-1Rs, and not peripheral GLP-1Rs, including vagal GLP1Rs, are necessary for liraglutide-induced weight loss (48). Our data from AP-lesioned animals are also in line with recent data from Baraboi et al demonstrating that the anorectic response to a single injection of exendin-4 was intact in AP-lesioned rats (37). Although the most readily accessible GLP-1Rs (vagal and AP) do not appear to be responsible for the long-term weight-reducing effects of liraglutide, it should be noted that peripherally accessible GLP-1-binding sites have been detected in the NTS located just beneath the AP (28).…”

Section: Discussionsupporting

confidence: 92%

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The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Secher¹,

Jelsing²,

Baquero³

et al. 2014

J. Clin. Invest.

722

673

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Section: Discussionsupporting

confidence: 92%

“…Numerous comprehensive studies aim to describe the GLP-1R population responsible for GLP-1-induced energy intake reduction (20,(33)(34)(35)(36)(37)(38)(39)(40)(41). This task has been hampered by the widespread distribution of the GLP-1R in the brain and in the periphery on neurons that could rapidly signal to the brain.…”

Section: Discussionmentioning

confidence: 99%

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Secher¹,

Jelsing²,

Baquero³

et al. 2014

J. Clin. Invest.

722

673

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“…CRF hnRNA is not constitutively produced in the brain, but its expression can be rapidly triggered in response to effective stimuli (5,22,49). It is noteworthy that the threshold dose necessary to stimulate CRF hnRNA expression (0.775 g/kg) was higher than the dose required for inducing a significant increase in plasma corticosterone (0.155 g/kg).…”

Section: Discussionmentioning

confidence: 96%

“…It has previously been suggested that the effect could be mediated through the activation of two specific circumventricular organs (CVOs), the AP and the subfornical organ (SFO) (10,23). Those two CVOs are known for their blood-brain barrier permeability and their high level of GLP-1R expression, and we recently reported that electrolytic ablation of AP and SFO alters Ex-4-induced c-fos expression in brain areas involved in the regulation of energy balance and associated behaviors (5). In parallel, contribution of the vagus nerve in GLP-1R agonist action has also been addressed by various groups (1,20,46,53).…”

mentioning

confidence: 99%

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

Baraboi

St-Pierre

Shooner

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 g/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 g/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 g/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 g/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.

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“…Indeed, both exendin-4 (Ex4) and liraglutide retained their food intake inhibitory effect after vagotomy, suggesting that they act directly in the brain (43). Similarly, another study found no effect of AP lesioning on food intake reduction by Ex4 (7). A recent elegant study by Secher et al (86) has gone some way further to address this question.…”

Section: Treatment With Glp-1 Analogsmentioning

confidence: 99%

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

Trapp

Cork

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Within the brain, glucagon-like peptide-1 (GLP-1) affects central autonomic neurons, including those controlling the cardiovascular system, thermogenesis, and energy balance. Additionally, GLP-1 influences the mesolimbic reward system to modulate the rewarding properties of palatable food. GLP-1 is produced in the gut and by hindbrain preproglucagon (PPG) neurons, located mainly in the nucleus tractus solitarii (NTS) and medullary intermediate reticular nucleus. Transgenic mice expressing glucagon promoter-driven yellow fluorescent protein revealed that PPG neurons not only project to central autonomic control regions and mesolimbic reward centers, but also strongly innervate spinal autonomic neurons. Therefore, these brain stem PPG neurons could directly modulate sympathetic outflow through their spinal inputs to sympathetic preganglionic neurons. Electrical recordings from PPG neurons in vitro have revealed that they receive synaptic inputs from vagal afferents entering via the solitary tract. Vagal afferents convey satiation to the brain from signals like postprandial gastric distention or activation of peripheral GLP-1 receptors. CCK and leptin, short-and long-term satiety peptides, respectively, increased the electrical activity of PPG neurons, while ghrelin, an orexigenic peptide, had no effect. These findings indicate that satiation is a main driver of PPG neuronal activation. They also show that PPG neurons are in a prime position to respond to both immediate and long-term indicators of energy and feeding status, enabling regulation of both energy balance and general autonomic homeostasis. This review discusses the question of whether PPG neurons, rather than gut-derived GLP-1, are providing the physiological substrate for the effects elicited by central nervous system GLP-1 receptor activation. appetite; brain stem; glucagon-like peptide-1; hippocampus; neuroanatomy FOR TWO DECADES, IT HAS BEEN known that glucagon-like peptide (GLP-1) reduces food intake by acting within the central nervous system (95). That first study showed through the use of the GLP-1 receptor antagonist exendin-9 (Ex9) that endogenous GLP-1 has the ability to suppress food intake and that this effect is dependent on the feeding state of the animal. While unequivocally showing that GLP-1 has a physiological role in brain, the source of centrally acting GLP-1 remains less clear. Does postprandially released GLP-1 from the enteroendocrine L-cells reach the central nervous system (CNS) from the circulation, despite its short half-life in the blood, or does the small number of preproglucagon (PPG) neurons in the lower brain stem (37,58,65) provide sufficient GLP-1 for the plethora of brain regions that express its receptor? Although this question remains largely unanswered, it is clear that central GLP-1 is integral to many more processes linked to energy homeostasis than simply food intake. This review provides a detailed account of the different actions of GLP-1 in the brain, with a particular emphasis on the potential role of the PPG...

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Lesions of area postrema and subfornical organ alter exendin-4-induced brain activation without preventing the hypophagic effect of the GLP-1 receptor agonist

Cited by 38 publications

References 69 publications

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation

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