Incretin receptor agonism rapidly inhibits AgRP neurons to suppress food intake in mice
Open accessAbstract
The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation antiobesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects.
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Both GIP and GLP-1 analogs at pharmacologic doses inhibit AgRP neurons in proportion to their anorexigenic action.
“McMorrow HE et al. using in vivo fiber photometry demonstrated that both GIP and GLP-1 analogs at pharmacologic doses inhibited AgRP neurons in proportion to their anorexigenic action.”
From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [46]
The Results section ('GIPR and GLP-1R analogs acutely inhibit AgRP neurons'; page unavailable) reports that pharmacologic doses of both analogs inhibited AgRP neurons in mice, measured by fiber photometry. The reported correlation with feeding suppression concerns a different measure: how much pretreatment blunted the neurons’ subsequent response to food presentation. The paper does not establish that the initial drug-induced inhibition was proportional to anorexigenic action. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDual GIP and GLP-1 receptor agonists more potently inhibit AgRP neurons and suppress food intake than either agonist alone.
“Notably, dual GIP and GLP-1 receptor agonists produced more potently inhibited AgRP neurons and suppressed food intake than either agonist alone (46).”
From GLP-1 agonists and exercise: the future of lifestyle prioritization (2025) · cites this paper as [46]
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A Mechanistic Rationale for Incretin-Based Therapeutics in the Management of Obesity
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AgRP neurons are required for the weight-lowering effects of GLP-1 receptor agonists in female mice
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GIP receptor agonism suppresses inflammation-induced aversion and food intake via distinct circuits
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IL-1β engages distinct peripheral sensory circuits to suppress feeding across timePreprint
Hayes, N. W., Xia, J. L., Frydman, J. A., Duran, M. J., Gebis, K. K., Lorch, C. M., Province, H. S., Tang, E., & Beutler, L. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.23.707454
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- Authors
- McMorrow, H. E., Cohen, A. B., Lorch, C. M., Hayes, N. W., Fleps, S. W., Frydman, J. A., Xia, J. L., Samms, R. J., & Beutler, L. R.
- Affiliations
- Northwestern University (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Beutler, Lisa R.
- Venue
- Journal of Clinical Investigation
- Published
- 2025-08-26
- Volume
- 135
- Issue
- 21
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC12578400
- OpenAlex
- W4413682611
- Cited by
- 12
- References
- 65
- Citations by year
- 2026: 11 · 2025: 1
- FWCI
- 5.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- NIH (P30-DK020595,K08-DK118188,R01-DK128477)
- American Diabetes Association (12-22-ACE-31)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- incretin receptor agonists, semaglutide, tirzepatide, AgRP neurons, food intake regulation, appetite, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, GLP-1 receptor agonism, gut-brain signaling, obesity, anorectic effect, fiber photometry
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, Animals, Eating, Glucagon-Like Peptides, Gastric Inhibitory Polypeptide, Male, Neurons, Receptors, Gastrointestinal Hormone, Mice, Glucagon-Like Peptide 1, Agouti-Related Protein, Incretins
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