A genetic map of the mouse dorsal vagal complex and its role in obesity

Nat Metab. 2021 Apr;3(4):530-545. doi: 10.1038/s42255-021-00363-1. Epub 2021 Mar 25.

Abstract

The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons-one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor (Calcr). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr, and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite / genetics
  • Body Weight / genetics
  • Brain Stem / physiopathology
  • Calcitonin Receptor-Like Protein / genetics
  • Cell Nucleus / genetics
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosome Mapping*
  • Gene Expression
  • Glucagon-Like Peptide-1 Receptor / antagonists & inhibitors
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons
  • Obesity / genetics*
  • Obesity / physiopathology*
  • Solitary Nucleus / physiology
  • Vagus Nerve / physiopathology*

Substances

  • Calcitonin Receptor-Like Protein
  • Calcrl protein, mouse
  • Chromatin
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor