Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure
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Background & aims Gut-derived peptides including ghrelin, cholecystokinin (CCK), peptide YY (PYY), glucagon-like peptide (GLP-1), and GLP-2 exert overlapping actions on energy homeostasis through defined G-protein-coupled receptors (GPCRs). The proglucagon-derived peptide (PGDP) oxyntomodulin (OXM) is cosecreted with GLP-1 and inhibits feeding in rodents and humans; however, a distinct receptor for OXM has not been identified.Methods We examined the mechanisms mediating oxyntomodulin action using stable cell lines expressing specific PGDP receptors in vitro and both wild-type and knockout mice in vivo.Results OXM activates signaling pathways in cells through glucagon or GLP-1 receptors (GLP-1R) but transiently inhibits food intake in vivo exclusively through the GLP-1R. Both OXM and the GLP-1R agonist exendin-4 (Ex-4) activated neuronal c-fos expression in the paraventricular nucleus of the hypothalamus, the area postrema, and the nucleus of the solitary tract following intraperitoneal (i.p.) injection. However, OXM transiently inhibited food intake in wild-type mice following intracerebroventricular (i.c.v.) but not i.p. administration, whereas Ex-4 produced a more potent and sustained inhibition of food intake following both i.c.v. and i.p. administration. The anorectic effects of OXM were preserved in Gcgr(-/-) mice but abolished in GLP-1R(-/-) mice. Although central Ex-4 and OXM inhibited feeding via a GLP-1R-dependent mechanism, Ex-4 but not OXM reduced VO2 and respiratory quotient in wild-type mice.Conclusions These findings demonstrate that structurally distinct PGDPs differentially regulate food intake and energy expenditure by interacting with a GLP-1R-dependent pathway. Hence ligand-specific activation of a common GLP-1R increases the complexity of gut-central nervous system pathways regulating energy homeostasis and metabolic expenditure.
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Intraventricular administration of GLP-1, GLP-2, and OXM significantly reduces food intake in mice.
“Experiments on mice have shown that intraventricular administration of GLP-1, GLP-2, and OXM could significantly reduce food intake (25, 26).”
From GLP−1 receptor agonists for the treatment of obesity: Role as a promising approach (2023) · cites this paper as [26]
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Perspectives in weight control in diabetes - survodutide
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- Authors
- Baggio, L. L., Huang, Q., Brown, T. J., & Drucker, D. J.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- Corresponding author
- Drucker, Daniel J.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2004-08
- Volume
- 127
- Issue
- 2
- Pages
- 546-558
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2171857877
- Cited by
- 372
- References
- 72
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 8 · 2023: 18 · 2022: 6 · 2021: 17 · 2020: 14 · 2019: 9 · 2018: 17 · 2017: 9 · 2016: 21 · 2015: 16 · 2014: 21 · 2013: 27 · 2012: 27
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- oxyntomodulin, glucagon-like peptide-1, proglucagon-derived peptides, GLP-1 receptor, dietary intake, energy expenditure, exendin-4, energy homeostasis, hypothalamic neurons, Fos expression, gut-brain signaling, respiratory quotient
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Amino Acid Sequence, Animals, Binding, Competitive, Brain, Cells, Cultured, Dose-Response Relationship, Drug, Eating, Energy Metabolism, Glucagon-Like Peptides, Glucagon, Cricetinae, Injections, Intraperitoneal, Injections, Intraventricular, Iodine Radioisotopes, Mice, Inbred C57BL, Molecular Sequence Data, Peptide Fragments, Peptides, Protein Precursors, Venoms, Proto-Oncogene Proteins c-fos, Receptors, Glucagon, Mice, Knockout, Receptors, G-Protein-Coupled, Mice, Rats, Glucagon-Like Peptide 1, Proglucagon, Glucagon-Like Peptide 2, Oxyntomodulin
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