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The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake

Abstract

The dorsomedial hypothalamic nucleus harbors leptin sensitive neurons and is intrinsically connected to hypothalamic nuclei involved in feeding behavior. However, it also receives ascending input from the visceroceptive neurons of the brainstem. We have identified a unique glucagon-like-peptide-2 containing neuronal pathway connecting the nucleus of the solitary tract with the dorsomedial hypothalamic nucleus. A glucagon-like-peptide-2 fiber plexus targets neurons expressing its receptor within the dorsomedial hypothalamic nucleus. Pharmacological and behavioral studies confirmed that glucagon-like-peptide-2 signaling is a specific transmitter inhibiting rodent feeding behavior and with potential long-term effects on body weight homeostasis. The glucagon-like-peptide-1 receptor antagonist, Exendin (9–39) is also a functional antagonist of centrally applied glucagon-like-peptide-2.

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Figure 1: Localizataion of GLP-2 neurons and the hypothalamic GLP-2 receptor mRNA.
Figure 2: Hypothalamic distribution of GLP-2R mRNA.
Figure 3: The anorectic effect of GLP-2 is pharmacological specific.
Figure 4: GLP-2 does not induce a conditioned taste aversion.

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Acknowledgements

The authors thank L. Thim and J.T. Clausen, Novo Nordisk, Bagsværd, Denmark, for helpful suggestions and for the gift of recombinant GLP-2 and GLP-2 antibody. J. Mandelbaum, Novo Nordisk A/S, Bagsværd, and G. Hahn, Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark, are deeply thanked for excellent technical assistance. This study was made possible by generous grants from the Danish Diabetes Association, The Novo Nordisk Foundation, The Danish Medical Research Council (# 9701798), The Danish Research Foundation to the Biotechnology Centre for Cellular Communication, Direktør Jacob og hustru Olga Madsen Foundation and Fonden til Laegevidenskabens fremme. M. Tang-Christensen is supported by a research grant from the Michaelsen Foundation.

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Correspondence to Mads Tang-Christensen.

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Tang-Christensen, M., Larsen, P., Thulesen, J. et al. The proglucagon-derived peptide, glucagon-like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med 6, 802–807 (2000). https://doi.org/10.1038/77535

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