Cited by 193Gastrointestinal motility and disordersRegulation of Appetite and ObesityNeuropeptides and Animal Physiology

An inter-organ neural circuit for appetite suppression

Open access
Zhang, Tong, Perkins, Matthew H., Chang, Hao, Han, Wenfei, de Araujo, Ivan E.·2022·Cell

Abstract

Glucagon-like peptide-1 (GLP-1) is a signal peptide released from enteroendocrine cells of the lower intestine. GLP-1 exerts anorectic and antimotility actions that protect the body against nutrient malabsorption. However, little is known about how intestinal GLP-1 affects distant organs despite rapid enzymatic inactivation. We show that intestinal GLP-1 inhibits gastric emptying and eating via intestinofugal neurons, a subclass of myenteric neurons that project to abdominal sympathetic ganglia. Remarkably, cell-specific ablation of intestinofugal neurons eliminated intestinal GLP-1 effects, and their chemical activation functioned as a GLP-1 mimetic. GLP-1 sensing by intestinofugal neurons then engaged a sympatho-gastro-spinal-reticular-hypothalamic pathway that links abnormal stomach distension to craniofacial programs for food rejection. Within this pathway, cell-specific activation of discrete neuronal populations caused systemic GLP-1-like effects. These molecularly identified, delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.

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Crossref · 10.1016/j.cell.2022.05.007

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  • GLP-1's action in the brain reduces appetite and may influence energy expenditure.

    “And GLP-1’s action in the brain reduces appetite and may influence energy expenditure.176,210,211”

    From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [176]

    The Results section reports that intracerebroventricular GLP-1 inhibited eating in mice, supporting the brain-action and appetite portion of the claim. The paper does not report an effect on energy expenditure; its experiments on intestinal GLP-1 instead identify local ileal receptors as necessary for those appetite-suppressing effects. No page numbers are available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • GLP-1 initiates signaling by binding to its receptor, GLP-1R, which is a G-protein-coupled receptor.

    “GLP-1 initiates signaling by binding to its receptor, GLP-1R, which is a G-protein-coupled receptor.176,177”

    From Glucagon-like peptide-1 receptor: mechanisms and advances in therapy (2024) · cites this paper as [176]

    The Introduction identifies GLP-1R as the receptor for GLP-1 analogs, and the Results show that ileal GLP-1 effects depend on GLP-1R signaling. Our copy does not state that GLP-1R is a G-protein-coupled receptor or describe GLP-1 binding to it as the initiating step. (LLM, conf=0.84)

    Experimental — accuracy not yet measured
  • Ileal GLP-1-evoked gastric distension suppressed eating via a spinal afferent pathway to the parasubthalamic nucleus and a brainstem premotor circuit controlling orofacial food rejection behavior, rather than via the canonical mechanosensory vagal afferent pathway.

    “Interestingly, rather than acting via the canonical mechanosensory VAN pathway (23), ileal GLP-1-evoked gastric distension suppressed eating via a spinal afferent pathway to the parasubthalamic nucleus and a brainstem premotor circuit controlling orofacial food rejection behavior.”
  • The intestinofugal pathway connects GLP-1R-expressing enteric neurons to stomach-innervating sympathetic neurons which inhibit gastric emptying and eating by a nitric oxide neuron-mediated increase in gastric distension.

    “This intestinofugal pathway connects GLP-1R-expressing enteric neurons to stomach-innervating sympathetic neurons which inhibit gastric emptying and eating by a potent nitric oxide neuron-mediated increase in gastric distension.”
  • Zhang et al. mapped a GLP-1-dependent inter-organ circuit from ileal L-cells to the brain that underlies the ileal brake.

    “A recent study by Zhang et al (44) elegantly delineated the neural circuit basis for this ileal brake, mapping a GLP-1-dependent inter-organ circuit from ileal L-cells to the brain.”

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Authors
Zhang, T., Perkins, M. H., Chang, H., Han, W., & de Araujo, I. E.
Affiliations
  • Jinan University (CN)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Han, Wenfei
Venue
Cell
Publisher
Elsevier BV
Published
2022-07
Volume
185
Issue
14
Pages
2478-2494.e28
ISSN
0092-8674 (ISSN-L)
OpenAlex
W4281724694
Cited by
192
References
88
Citations by year
2026: 42 · 2025: 53 · 2024: 45 · 2023: 36 · 2022: 16
FWCI
33.02
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (P20NS123220)
  • National Center for Complementary and Integrative Health (R01AT011697)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
glucagon-like peptide-1, appetite suppression, myenteric neurons, enteric nervous system, gastric emptying, hypothalamic pathways, food refusal, bloating, gastric motility disorders
MeSH terms
Abdomen, Glucagon-Like Peptide-1 Receptor, Animals, Appetite, Cell Communication, Ileum, Male, Neurons, Nitric Oxide, Stomach, Signal Transduction, Mice, Glucagon-Like Peptide 1

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