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

Abstract

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.

Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

“…Both exendin-4 [8] and liraglutide [7] can cross the blood-brain-barrier. Previous data has shown that peripheral administration of exendin-4 activates both the PVN and arcuate and that this activation is through a combination of vagal and direct CNS action [1]. Consistent with these previous reports, our data shows that central administration of both liraglutide and exendin-4 increase neuronal activity in the PVN and arcuate nuclei.…”

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

“…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.…”

Parabrachial Nucleus Contributions to Glucagon-Like Peptide-1 Receptor Agonist-Induced Hypophagia

“…Recent studies have documented direct monosynaptic connections between GLP-1-producing neurons in the NST and the PBN , and both GLP-1R mRNA and GLP-1-immunopositive fibers have been identified within the PBN (Merchenthaler et al, 1999;Rinaman, 2010). Studies have also shown that peripheral doses of Ex4 stimulate Fos mRNA in PBN neurons, predominantly in the external lateral subnucleus of the PBN (Baraboi et al, 2011) that is commonly associated with processing of visceral afferent stimuli (Baird et al, 2001a, b;Fulwiler and Saper, 1984;Karimnamazi et al, 2002;Paues et al, 2006). It is worth noting that subdiaphragmatic vagotomy did not attenuate systemic Ex4-induced PBN Fos expression in the latter study, suggesting that the PBN might be activated directly by Ex4 (Kanoski et al, 2011), as Ex4 is also known to rapidly cross the blood-brain barrier (Kastin and Akerstrom, 2003).…”