GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence

• DOI: 10.1210/en.2014-1248
• Publication Date: 2014-08-13T17:20:30Z
• Authors: Jennifer E. Richard; Imre Farkas; Fredrik Anesten; Rozita H. Anderberg; Suzanne L. Dickson; Fiona M. Gribble; Frank Reimann; John-Olov Jansson; Zsolt Liposits; Karolina P. Skibicka
• Keywords: Male; Neurons; 0301 basic medicine; 2. Zero hunger; Appetite Regulation; Hypothalamus; Down-Regulation; Mice, Transgenic; Feeding Behavior; Parabrachial Nucleus; Glucagon-Like Peptide-1 Receptor; Electrophysiological Phenomena; Rats; Rats, Sprague-Dawley; Eating; Mice; 03 medical and health sciences; Glucagon-Like Peptide 1; Receptors, Glucagon; Animals; Female

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.