title: GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence.
abstract: The parabrachial nucleus (PBN) is a key nucleus for the regulation of feeding behavior. Inhibitory inputs from the hypothalamus to the PBN play a crucial role in the normal maintenance of feeding behavior, because their loss leads to starvation. Viscerosensory stimuli result in neuronal activation of the PBN. However, the origin and neurochemical identity of the excitatory neuronal input to the PBN remain largely unexplored. Here, we hypothesize that hindbrain glucagon-like peptide 1 (GLP-1) neurons provide excitatory inputs to the PBN, activation of which may lead to a reduction in feeding behavior. Our data, obtained from mice expressing the yellow fluorescent protein in GLP-1-producing neurons, revealed that hindbrain GLP-1-producing neurons project to the lateral PBN (lPBN). Stimulation of lPBN GLP-1 receptors (GLP-1Rs) reduced the intake of chow and palatable food and decreased body weight in rats. It also activated lPBN neurons, reflected by an increase in the number of c-Fos-positive cells in this region. Further support for an excitatory role of GLP-1 in the PBN is provided by electrophysiological studies showing a remarkable increase in firing of lPBN neurons after Exendin-4 application. We show that within the PBN, GLP-1R activation increased gene expression of 2 energy balance regulating peptides, calcitonin gene-related peptide (CGRP) and IL-6. Moreover, nearly 70% of the lPBN GLP-1 fibers innervated lPBN CGRP neurons. Direct intra-lPBN CGRP application resulted in anorexia. Collectively, our molecular, anatomical, electrophysiological, pharmacological, and behavioral data provide evidence for a functional role of the GLP-1R for feeding control in the PBN.
authors.affiliation: Department of Physiology/Metabolic Physiology (J.E.R., R.H.A., K.P.S.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-40530, Sweden; Laboratory of Endocrine Neurobiology (I.F., Z.L.), Institute of Experimental Medicine, Budapest 1083, Hungary; Department of Physiology/Endocrinology (F.A., S.L.D., J.-O.J.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg SE-40530, Sweden; and Cambridge Institute for Medical Research and Wellcome Trust-Medical Research Council Institute of Metabolic Science (F.M.G., F.R.), University of Cambridge, Cambridge CB2 2XY, United Kingdom.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Richard
authors.forename: Imre
authors.initials: I
authors.lastname: Farkas
authors.forename: Fredrik
authors.initials: F
authors.lastname: Anesten
authors.forename: Rozita H
authors.initials: RH
authors.lastname: Anderberg
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Dickson
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.forename: John-Olov
authors.initials: JO
authors.lastname: Jansson
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Liposits
authors.forename: Karolina P
authors.initials: KP
authors.lastname: Skibicka
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004435:Eating / Q000187:drug effects*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D007031:Hypothalamus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D065823:Parabrachial Nucleus / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists*
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1