A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss.
Animals
Neurons
/ metabolism
Insulin
/ metabolism
Caenorhabditis elegans
/ metabolism
Homeostasis
Caenorhabditis elegans Proteins
/ metabolism
Receptor, Insulin
/ metabolism
Signal Transduction
/ drug effects
Brain
/ metabolism
Neuropeptides
/ metabolism
Forkhead Transcription Factors
/ metabolism
Intestines
Phylogeny
Fasting
Intestinal Mucosa
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
11 Aug 2024
11 Aug 2024
Historique:
received:
29
09
2023
accepted:
29
07
2024
medline:
11
8
2024
pubmed:
11
8
2024
entrez:
10
8
2024
Statut:
epublish
Résumé
In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions.
Identifiants
pubmed: 39127676
doi: 10.1038/s41467-024-51077-3
pii: 10.1038/s41467-024-51077-3
doi:
Substances chimiques
Insulin
0
Caenorhabditis elegans Proteins
0
Receptor, Insulin
EC 2.7.10.1
Neuropeptides
0
DAF-2 protein, C elegans
EC 2.7.10.1
Forkhead Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6869Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK124706
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056648
Pays : United States
Informations de copyright
© 2024. The Author(s).
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