title: Glucagon-like peptide-1-responsive catecholamine neurons in the area postrema link peripheral glucagon-like peptide-1 with central autonomic control sites.
abstract: Glucagon-like peptide-1 (GLP-1) released from the gut is an incretin that stimulates insulin secretion. GLP-1 is also a brain neuropeptide that has diverse central actions, including inhibition of food and water intake, gastric emptying, and stimulation of neuroendocrine responses characteristic of visceral illness. Both intravenous and intracerebroventricular administration of GLP-1 receptor (GLP-1R) agonists increase blood pressure and heart rate and induce Fos-like immunoreactivity (Fos-IR) in autonomic regulatory sites in the rat brain. The area postrema (AP) is a circumventricular organ and has been implicated in processing visceral sensory information. GLP-1Rs are densely expressed in the AP, and peripheral GLP-1R agonists induce Fos-IR in AP neurons to a greater degree than intracerebroventricular administration. Because the AP lacks a blood-brain barrier, we hypothesized that the AP is a key site for peripheral GLP-1 to activate central autonomic regulatory sites. In this study, we found that many tyrosine hydroxylase (TH)-containing neurons in the AP expressed GLP-1Rs and Fos-IR after intravenous GLP-1R agonists. Furthermore, intravenous but not intracerebroventricular GLP-1R agonists induced TH transcription in the AP in vivo. In addition, GLP-1R agonists directly activated TH transcription in an in vitro cell system. Finally, we found that GLP-1-responsive TH neurons in the AP innervate autonomic control sites, including the parabrachial nucleus, nucleus of solitary tract, and ventrolateral medulla. These findings suggest that catecholamine neurons in the AP link peripheral GLP-1 and central autonomic control sites that mediate the diverse neuroendocrine and autonomic actions of peripheral GLP-1.
authors.affiliation: Department of Medicine and Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Kishi
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Choi
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Hollenberg
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
mesh_terms: D000818:Animals; D031608:Area Postrema / Q000166:cytology*; D017776:Autonomic Pathways / Q000166:cytology*; D002395:Catecholamines / Q000096:biosynthesis; D002460:Cell Line; D002490:Central Nervous System / Q000166:cytology*; D000077270:Exenatide; D005934:Glucagon / Q000502:physiology; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D017552:Solitary Nucleus / Q000166:cytology; D015533:Transcriptional Activation; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D014688:Venoms
chemical_list: D002395:Catecholamines; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D012333:RNA, Messenger; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D014446:Tyrosine 3-Monooxygenase