Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism

Cell Metab. 2021 Jul 6;33(7):1466-1482.e7. doi: 10.1016/j.cmet.2021.05.002. Epub 2021 May 26.


Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control.

Keywords: Dre-recombinase; appetite; chemogenetics; dorsal root ganglion; glucose metabolism; gut-brain axis; intersectional genetics; nodose ganglion; sensory neurons; vagus nerve.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afferent Pathways / metabolism
  • Animals
  • Appetite / physiology
  • Appetite Regulation* / genetics
  • Brain-Gut Axis / physiology*
  • Cell Communication / genetics
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • Glucagon-Like Peptide-1 Receptor / genetics
  • Glucagon-Like Peptide-1 Receptor / metabolism
  • Glucose / metabolism*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Male
  • Mice, Transgenic
  • Nodose Ganglion / metabolism
  • Nodose Ganglion / physiology
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Sensory Receptor Cells / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Vagus Nerve / metabolism
  • Vagus Nerve / physiology
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism


  • GPR65 protein, mouse
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Homeodomain Proteins
  • Phox2b protein, mouse
  • Receptors, G-Protein-Coupled
  • Transcription Factors
  • Wnt1 Protein
  • Wnt1 protein, mouse
  • Glucose