Expression of glucagon-like peptide 1 receptor in neuropeptide Y neurons of the arcuate nucleus in mice

Brain Struct Funct. 2022 Jan;227(1):77-87. doi: 10.1007/s00429-021-02380-y. Epub 2021 Oct 1.

Abstract

Glucagon-like peptide 1 (GLP-1) and its agonists exert anorexigenic effect at least partly via acting on GLP-1 receptors (GLP-1R) in the arcuate nucleus (ARC). While the anorexigenic, proopiomelanocortin (POMC) neurons of the ARC were shown previously to express GLP-1R, the putative GLP-1R-content of the orexigenic, neuropeptide Y (NPY) neurons remained so far undetected. As GLP-1R is abundant in the ventromedial ARC, where NPY neurons are located; here, we address the possibility that GLP-1 can act directly on the orexigenic NPY system via GLP-1R. Double-labeling immunocytochemistry and in situ hybridization were performed on tissues of adult male mice to detect GLP-1R in NPY neurons. In double-immunolabeled preparations, GLP-1R-immunoreactivity was observed in NPY neurons and in axons ensheathing the majority of NPY neurons. Ultrastructural studies confirmed that GLP-1R-immunoreactivity is associated with the outer membrane of NPY perikarya as well as with axons forming symmetric type, inhibitory synapses on NPY-containing neurons. Double-labeling in situ hybridization experiments demonstrated the expression of GLP-1R mRNA in approximately 20% of NPY mRNA-containing neurons of the ARC. In summary, our data demonstrate the presence of GLP-1R protein and mRNA in NPY neurons of ARC and also reveal the innervation of NPY neurons by GLP-1R-containing inhibitory neurons. These observations suggest that GLP-1 signaling can influence NPY neurons both directly and indirectly. Furthermore, GLP-1 signaling on energy homeostasis appears to involve both direct and indirect effects of GLP-1 on the orexigenic NPY neurons, in addition to the previously known effects via the anorexigenic POMC neuronal system.

Keywords: Arcuate nucleus; Energy homeostasis; Glucagon-like peptide 1 receptor; Neuropeptide Y.

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus* / metabolism
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Male
  • Mice
  • Neurons / metabolism
  • Neuropeptide Y / genetics
  • Neuropeptide Y / metabolism
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • RNA, Messenger

Substances

  • Glucagon-Like Peptide-1 Receptor
  • Neuropeptide Y
  • RNA, Messenger
  • Pro-Opiomelanocortin
  • Glucagon-Like Peptide 1